TW202214873A - Biomarkers and uses thereof in the treatment of chronic hbv infection - Google Patents

Biomarkers and uses thereof in the treatment of chronic hbv infection Download PDF

Info

Publication number
TW202214873A
TW202214873A TW110132421A TW110132421A TW202214873A TW 202214873 A TW202214873 A TW 202214873A TW 110132421 A TW110132421 A TW 110132421A TW 110132421 A TW110132421 A TW 110132421A TW 202214873 A TW202214873 A TW 202214873A
Authority
TW
Taiwan
Prior art keywords
hla
hed
gene
viral
therapy
Prior art date
Application number
TW110132421A
Other languages
Chinese (zh)
Inventor
瑪麗安 伊莎貝爾 杜費爾
瑪喬琳 克拉布
雅克 亞曼德 亨利 布列肯斯
傑羅恩 瑪賽爾 瑪麗亞 羅傑 艾森斯
卡拉 亞歷山大 帝
Original Assignee
愛爾蘭商健生科學愛爾蘭無限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 愛爾蘭商健生科學愛爾蘭無限公司 filed Critical 愛爾蘭商健生科學愛爾蘭無限公司
Publication of TW202214873A publication Critical patent/TW202214873A/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
    • C12Q1/701—Specific hybridization probes
    • C12Q1/706—Specific hybridization probes for hepatitis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6881—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for tissue or cell typing, e.g. human leukocyte antigen [HLA] probes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Wood Science & Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Analytical Chemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Cell Biology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Immunogenetic biomarkers of viral control of chronic hepatitis B (CHB) infection that are indicative of relapse after a viral suppression treatment, such as a NUC treatment, in CHB infected subject are described. Also described are methods and compositions of using the immunogenetic biomarkers in predicting the relapse in the viral suppression treatment of CHB infection.

Description

生物標記及其於治療慢性HBV感染之用途Biomarkers and their use in the treatment of chronic HBV infection

本發明大體上係關於慢性HBV感染(CHB)之病毒控制之免疫遺傳生物標記及於治療CHB之相關用途。The present invention generally relates to immunogenetic biomarkers for viral control of chronic HBV infection (CHB) and related uses in the treatment of CHB.

由B型肝炎病毒(HBV)引起之慢性感染影響全球約4億人且係全球主要死亡原因之一。肝病研究協會(Association for the Study of Liver Disease；AASLD)指南建議對於出現血清HBV DNA濃度高於2,000 IU/mL及/或丙胺酸胺基轉移酶(ALT)濃度升高(＞正常上限的2倍)的患者進行治療。Chronic infection caused by hepatitis B virus (HBV) affects approximately 400 million people worldwide and is one of the leading causes of death worldwide. Association for the Study of Liver Disease (AASLD) guidelines recommend that patients with serum HBV DNA concentrations greater than 2,000 IU/mL and/or elevated alanine aminotransferase (ALT) concentrations (>2 times the upper limit of normal) ) patients were treated.

慢性B型肝炎(CHB)之抗病毒療法旨在降低肝臟相關致病率及死亡率。持續抑制HBV複製的達成與血清丙胺酸轉胺酶(ALT)的正常化、B型肝炎e-抗原(HBeAg)的喪失(具有或不具有抗-HBe的偵測)及肝組織學的改良相關聯。該目標可藉由例如用聚乙二醇化干擾素(Peg-IFN)的短期治療或用口服核苷酸或核苷類似物(NUC)的長期抑制療法來達成(Lok & McMahon，Hepatology，2009，50: 661–662；EASL clinical practice guidelines: management of chronic hepatitis B，J. Hepatol.，2012，57:167–185)。最近，口服投與NUC已成為全球最受歡迎的治療策略，因為第三代NUC(諸如恩替卡韋(entecavir)及替諾福韋(tenofovir))的極佳功效及安全性，不僅在註冊試驗中而且在臨床實務中亦如此。Antiviral therapy for chronic hepatitis B (CHB) aims to reduce liver-related morbidity and mortality. Sustained suppression of HBV replication is associated with normalization of serum alanine transaminase (ALT), loss of hepatitis B e-antigen (HBeAg) (with or without detection of anti-HBe), and improvement in liver histology link. This goal can be achieved by, for example, short-term treatment with pegylated interferon (Peg-IFN) or long-term suppressive therapy with oral nucleotide or nucleoside analogs (NUCs) (Lok & McMahon, Hepatology, 2009, 50: 661-662; EASL clinical practice guidelines: management of chronic hepatitis B, J. Hepatol., 2012, 57: 167-185). Recently, the oral administration of NUCs has become the most popular treatment strategy worldwide due to the excellent efficacy and safety of third-generation NUCs, such as entecavir and tenofovir, not only in registered trials but also The same is true in clinical practice.

口服抗病毒NUC可規定為每天一次口服給藥，副作用最小，且在病毒抑制及肝酶的正常化上極有效。然而，大多數患者需要長期療法且在過早停止療法後病毒學復發係常見的(Ahn等人，Hepatol.Int.，2010，4: 386–95；van Nunen等人，Gut.，2003，52: 420-442)。Oral antiviral NUCs can be prescribed for once-daily oral administration with minimal side effects and are extremely effective in viral suppression and normalization of liver enzymes. However, most patients require long-term therapy and virological relapse is common after premature cessation of therapy (Ahn et al., Hepatol. Int., 2010, 4: 386-95; van Nunen et al., Gut., 2003, 52 : 420-442).

B型肝炎表面抗原(HBsAg)的清除係停止治療的理想終點，但用抗病毒療法後5年內其出現通常低於5%。有關停止治療的建議取決於不同組之CHB患者。儘管如此，即使遵循此等建議，約25%至50%的患者仍可在停止NUC療法後發展肝炎復發(Fung等人，Am. J. Gastroenterol 2009；104: 1940–6；Hadziyannis等人，Hepatology 2006，1: 231A)。Hepatitis B surface antigen (HBsAg) clearance is an ideal endpoint for treatment discontinuation, but its occurrence is usually less than 5% within 5 years of antiviral therapy. Recommendations for discontinuation of treatment depend on different groups of CHB patients. Nonetheless, even following these recommendations, approximately 25% to 50% of patients develop hepatitis relapse upon discontinuation of NUC therapy (Fung et al, Am. J. Gastroenterol 2009;104: 1940–6; Hadziyannis et al, Hepatology 2006, 1: 231A).

因此，希望能夠預測患者對CHB療法的反應，且然後從一開始就相應調整治療策略，以便將治療終止之後復發的風險最小化。特別地，該預測較佳基於偵測CHB之病毒控制之免疫遺傳生物標記。Therefore, it is desirable to be able to predict a patient's response to CHB therapy and then adjust the treatment strategy accordingly from the outset in order to minimize the risk of relapse after treatment discontinuation. In particular, the prediction is preferably based on immunogenetic biomarkers that detect viral control of CHB.

前述討論的呈現僅為了更佳地理解此項技術所面臨的問題的本質且不應以任何方式解釋為承認先前技術，亦不應將本文中任何參考之引用解釋為承認此類參考構成本申請案之「先前技術」。The foregoing discussion is presented only for a better understanding of the nature of the problems faced by the art and should not be construed in any way as an admission of prior art, nor should the citation of any reference herein be construed as an admission that such reference constitutes the present application "Prior Art" in the case.

本發明提供CHB之病毒控制之免疫遺傳生物標記於治療CHB患者之識別及用途。The present invention provides the identification and use of immunogenetic biomarkers of viral control of CHB in the treatment of CHB patients.

在一個一般態樣中，本申請案係關於一種判定患有慢性B型肝炎(CHB)感染的個體在病毒抑制治療中止之後是否具有高或低復發機率，較佳地在中止之後兩年時間內是否具有高或低復發機率之方法，該方法包括： a. 偵測從該個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i. 人類白血球抗原(HLA)對偶基因； ii. 一或多個HLA-C單核苷酸多型性(SNP)； iii. HLA演化多樣性(HED)分數；及 iv. 白血球受體複合物(LCR) SNP； b. 若在生物樣本中偵測到一或多個免疫遺傳生物標記，則判定個體之復發機率為低，或若在生物樣本中未偵測到免疫遺傳生物標記，則判定個體之復發機率為高。 In a general aspect, the present application relates to a method for determining whether an individual with chronic hepatitis B (CHB) infection has a high or low chance of relapse following discontinuation of viral suppressive therapy, preferably within two years of discontinuation Whether there is a high or low chance of recurrence, the method includes: a. Detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. Human leukocyte antigen (HLA) pair genes; ii. One or more HLA-C single nucleotide polytypes (SNPs); iii. HLA Evolutionary Diversity (HED) score; and iv. Leukocyte receptor complex (LCR) SNPs; b. If one or more immunogenetic biomarkers are detected in the biological sample, the probability of recurrence of the individual is determined to be low, or if no immune genetic biomarkers are detected in the biological sample, the probability of recurrence of the individual is determined to be high.

在某些實施例中，免疫遺傳生物標記的偵測係在病毒抑制治療之前、期間或之後。In certain embodiments, the detection of immunogenetic biomarkers is before, during, or after viral suppressive therapy.

在某些實施例中，該病毒抑制治療係選自由替諾福韋、恩替卡韋、拉米夫定(lamivudine)、阿德福韋(adefovir)及替比夫定(telbivudine)組成之群之核苷酸或核苷(NUC)。In certain embodiments, the viral suppressive therapy is a nucleoside selected from the group consisting of tenofovir, entecavir, lamivudine, adefovir, and telbivudine acid or nucleoside (NUC).

在另一個一般態樣中，本申請案係關於一種治療有需要個體中慢性B型肝炎(CHB)感染之方法，該方法包括： a. 對該個體投與病毒抑制治療以治療CHB感染； b. 偵測從該個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i. 人類白血球抗原(HLA)對偶基因； ii. 一或多個HLA-C單核苷酸多型性(SNP)； iii. HLA演化多樣性(HED)分數；及 iv. 白血球受體複合物(LCR) SNP； c. 若在生物樣本中偵測到步驟b之該一或多個免疫遺傳生物標記，則一旦達成病毒抑制，立刻中止該病毒抑制治療，較佳地，該病毒抑制治療係在治療2年之後中止；或 若在生物樣本中未偵測到步驟b之免疫遺傳生物標記，則繼續該病毒抑制治療，甚至在達成病毒抑制之後，及/或對該個體投與一種另外或不同病毒抑制治療。 In another general aspect, the present application relates to a method of treating chronic hepatitis B (CHB) infection in an individual in need thereof, the method comprising: a. administering to the individual viral suppressive therapy to treat CHB infection; b. Detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. Human leukocyte antigen (HLA) pair genes; ii. One or more HLA-C single nucleotide polytypes (SNPs); iii. HLA Evolutionary Diversity (HED) score; and iv. Leukocyte receptor complex (LCR) SNPs; c. If the one or more immunogenetic biomarkers of step b are detected in the biological sample, once viral suppression is achieved, the viral suppressive treatment is immediately discontinued, preferably, the viral suppressive treatment is performed after 2 years of treatment suspend; or If the immunogenetic biomarker of step b is not detected in the biological sample, the viral suppression therapy is continued, even after viral suppression is achieved, and/or an additional or different viral suppression therapy is administered to the individual.

在某些實施例中，該病毒抑制治療係選自由替諾福韋、恩替卡韋、拉米夫定、阿德福韋及替比夫定組成之群之核苷酸或核苷(NUC)。In certain embodiments, the viral suppressive therapy is a nucleotide or nucleoside (NUC) selected from the group consisting of tenofovir, entecavir, lamivudine, adefovir, and telbivudine.

在某些實施例中，當個體達成HBV DNA ＜ 60 IU/mL、ALT ＜ 80 U/L及HBeAg陰性中之至少一者時，該個體中止病毒抑制治療。In certain embodiments, the individual discontinues viral suppression therapy when the individual achieves at least one of HBV DNA < 60 IU/mL, ALT < 80 U/L, and negative for HBeAg.

在某些實施例中，個體在病毒抑制治療中止之後3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後沒有病毒學復發或臨床復發，且其中該病毒學復發經識別為HBV DNA ≥ 2000 IU/ml或HBeAg陽性，及該臨床復發經識別為i) HBV DNA ≥ 2000 IU/ml或HBeAg陽性，且ii) ALT ≥ 80 U/L。In certain embodiments, the subject has no virological relapse at or after 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, or any time in between, after cessation of viral suppressive therapy or Clinical relapse where the virological relapse was identified as HBV DNA ≥ 2000 IU/ml or HBeAg positive, and the clinical relapse was identified as i) HBV DNA ≥ 2000 IU/ml or HBeAg positive, and ii) ALT ≥ 80 U /L.

在另一個一般態樣中，本申請案係關於一種治療有需要個體中慢性B型肝炎(CHB)感染之方法，該方法包括： a. 對該個體投與病毒抑制治療以治療CHB感染； b. 偵測從該個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i. 人類白血球抗原(HLA)對偶基因； ii. 一或多個HLA-C單核苷酸多型性(SNP)； iii. HLA演化多樣性(HED)分數；及 iv. 白血球受體複合物(LCR) SNP； c. 當個體中CHB感染得以抑制時，中止病毒抑制治療，及 d. 若在生物樣本中未偵測到免疫遺傳生物標記，則在中止之後少於兩年對該個體投與病毒抑制治療或另一病毒抑制治療。 In another general aspect, the present application relates to a method of treating chronic hepatitis B (CHB) infection in an individual in need thereof, the method comprising: a. administering to the individual viral suppressive therapy to treat CHB infection; b. Detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. Human leukocyte antigen (HLA) pair genes; ii. One or more HLA-C single nucleotide polytypes (SNPs); iii. HLA Evolutionary Diversity (HED) score; and iv. Leukocyte receptor complex (LCR) SNPs; c. Discontinue viral suppression therapy when CHB infection is suppressed in the individual, and d. If no immunogenetic biomarker is detected in the biological sample, administer viral suppressive therapy or another viral suppressive therapy to the individual less than two years after discontinuation.

在某些實施例中，該病毒抑制治療係選自由替諾福韋、恩替卡韋、拉米夫定、阿德福韋及替比夫定組成之群之核苷酸或核苷(NUC)。In certain embodiments, the viral suppressive therapy is a nucleotide or nucleoside (NUC) selected from the group consisting of tenofovir, entecavir, lamivudine, adefovir, and telbivudine.

在某些實施例中，當個體達成HBV DNA ＜ 60 IU/mL、ALT ＜ 80 U/L或HBeAg陰性時，該個體中止病毒抑制治療。In certain embodiments, the individual discontinues viral suppression therapy when the individual achieves HBV DNA < 60 IU/mL, ALT < 80 U/L, or negative HBeAg.

在某些實施例中，個體在病毒抑制治療中止之後3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後沒有病毒學復發或臨床復發，且其中該病毒學復發經識別為HBV DNA ≥ 2000 IU/ml或HBeAg陽性，及該臨床復發經識別為i) HBV DNA ≥ 2000 IU/ml或HBeAg陽性，且ii) ALT ≥ 80 U/L。In certain embodiments, the subject has no virological relapse at or after 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, or any time in between, after cessation of viral suppressive therapy or Clinical relapse where the virological relapse was identified as HBV DNA ≥ 2000 IU/ml or HBeAg positive, and the clinical relapse was identified as i) HBV DNA ≥ 2000 IU/ml or HBeAg positive, and ii) ALT ≥ 80 U /L.

在某些實施例中，樣本係選自組織樣本、細胞樣本、血液樣本。較佳地，樣本係血液樣本。In certain embodiments, the sample is selected from a tissue sample, a cell sample, and a blood sample. Preferably, the sample is a blood sample.

在某些實施例中，免疫遺傳生物標記包含HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在。In certain embodiments, the immunogenetic biomarker comprises the presence of HLA counterpart B*51 or C*15 or the absence of HLA counterpart C*07.

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之HLA-C SNP：rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、rs9264039及rs3868078或其互補序列。In certain embodiments, the immunogenetic biomarker comprises an HLA-C SNP selected from the group consisting of: rs2394952, rs3130542, rs2894202, rs9264523, rs1049281, rs9264643, rs1130838, rs2394888, AX-83089411, rs2308622, rs91640416, rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、 rs9264039 and rs3868078 or their complements.

在某些實施例中，該免疫遺傳生物標記包含至少一個大於選自下表之臨限值之HED分數： HLA 區域 HLA 基因 變數 臨限值 平均HLA I類 HLA-A HED_HLA_A_CAT_VR 3.88 平均HLA I類 HLA-B HED_HLA_B_CAT_VR 9.37 平均HLA I類 HLA-C HED_HLA_C_CAT_VR 0.00 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_VR 8.69 平均HLA II類 HLA-DPB1 HED_HLA_P_CAT_VR 2.21 平均HLA II類 HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_VR 12.68 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_VR 7.55 平均HLA I類 HLA-A HED_HLA_A_CAT_CR 3.88 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_CR 7.67 平均HLA I類 HLA-C HED_HLA_C_CAT_SCR 7.37 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_SCR 7.61 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_SCR 8.21 In certain embodiments, the immunogenetic biomarker comprises at least one HED score greater than a threshold value selected from the following table: HLA region HLA gene variable Threshold value Average HLA class I HLA-A HED_HLA_A_CAT_VR 3.88 Average HLA class I HLA-B HED_HLA_B_CAT_VR 9.37 Average HLA class I HLA-C HED_HLA_C_CAT_VR 0.00 Average HLA class I MEAN_MHCI HED_MEANI_CAT_VR 8.69 Average HLA class II HLA-DPB1 HED_HLA_P_CAT_VR 2.21 Average HLA class II HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_VR 12.68 Average HLA class II MEAN_MHCII HED_MEANII_CAT_VR 7.55 Average HLA class I HLA-A HED_HLA_A_CAT_CR 3.88 Average HLA class II MEAN_MHCII HED_MEANII_CAT_CR 7.67 Average HLA class I HLA-C HED_HLA_C_CAT_SCR 7.37 Average HLA class I MEAN_MHCI HED_MEANI_CAT_SCR 7.61 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 Average HLA class II MEAN_MHCII HED_MEANII_CAT_SCR 8.21

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之LCR SNP：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598、或其互補序列。In certain embodiments, the immunogenetic biomarker comprises an LCR SNP selected from the group consisting of: rs10426302, rs59537494, rs28366008, rs36625, rs635608, rs7595, rs731170, rs28513, rs12459334, rs11666535, rs4806807, rs39084367, rs39084367 rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、 rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、 rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598、或其互補序列。

在另一個態樣中，本文提供一種組合，其用於預測有需要個體中在治療慢性B型肝炎(CHB)感染之病毒抑制之後的低復發風險，該組合包含能夠偵測CHB感染的病毒控制之免疫遺傳生物標記中之一者或多者之試劑。In another aspect, provided herein is a combination for predicting a low risk of relapse following viral suppression in the treatment of chronic hepatitis B (CHB) infection in an individual in need thereof, the combination comprising viral control capable of detecting CHB infection A reagent for one or more of the immunogenetic biomarkers.

在又另一個態樣中，本文提供一種用於血清學HLA分型之套組、或用於遺傳學HLA分型之套組，諸如DNA晶片、PCR套組或一組PCR引子及/或探針，其用於預測病毒抑制劑於治療有需要個體中慢性B型肝炎(CHB)感染之功效。In yet another aspect, provided herein is a kit for serological HLA typing, or a kit for genetic HLA typing, such as a DNA chip, a PCR kit, or a set of PCR primers and/or probes needles for predicting the efficacy of viral inhibitors in the treatment of chronic hepatitis B (CHB) infection in individuals in need.

於閱讀本發明及申請專利範圍之以下詳細描述後，將更佳地瞭解本發明之其他態樣、特徵及優點。Other aspects, features and advantages of the present invention will be better understood after reading the following detailed description of the invention and the scope of the claims.

相關申請案之交叉參考Cross-references to related applications

本申請案主張2020年9月2日申請之美國臨時申請案第63/073,617號之優先權，該案之揭示內容係以全文引用之方式併入本文中。This application claims priority to US Provisional Application No. 63/073,617, filed on September 2, 2020, the disclosure of which is incorporated herein by reference in its entirety.

先前技術及本說明書通篇中引述或描述各種公開案、文章及專利；此等引用中之各者係以全文引用之方式併入本文中。已包括在本說明書中的文件、動作、材料、裝置、物件或類似者的討論係用於提供本發明之上下文之目的。此種討論並非承認任何或所有此等事項構成關於所揭示或所主張的任何發明之先前技術之一部分。Various publications, articles and patents are cited or described throughout the prior art and this specification; each of these citations is incorporated herein by reference in its entirety. Discussions of documents, acts, materials, devices, articles or the like that have been included in this specification are for the purpose of providing a context for the present invention. This discussion is not an admission that any or all of these matters form part of the prior art with respect to any invention disclosed or claimed.

除非另有定義，否則本文所使用的所有技術及科學術語具有與本發明所屬領域之一般技術者通常所理解相同的含義。否則，本文所使用的某些術語具有如本說明書中所述的含義。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Otherwise, certain terms used herein have the meanings as set forth in this specification.

必須注意，除非上下文另有明確指示，否則如本文及隨附申請專利範圍中所使用，單數形式「一」、「一個」及「該」包括複數指示物。It must be noted that, as used herein and in the scope of the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

除非另有說明，否則任何數值(諸如本文所述的濃度或濃度範圍)應理解為在所有情況下均由術語「約」修飾。因此，數值通常包括列舉值的± 10%。例如，1 mg/mL的濃度包括0.9 mg/mL至1.1 mg/mL。同樣地，1%至10% (w/v)的濃度範圍包括0.9% (w/v)至11% (w/v)。如本文所用，除非上下文另有明確指示，否則使用數值範圍明確包括所有可能的子範圍、該範圍內的所有個別數值，包括此類範圍內的整數及該等值的分數。Unless otherwise indicated, any numerical value, such as a concentration or concentration range described herein, should be understood to be modified in all instances by the term "about." Accordingly, numerical values generally include ± 10% of the recited value. For example, a concentration of 1 mg/mL includes 0.9 mg/mL to 1.1 mg/mL. Likewise, the concentration range of 1% to 10% (w/v) includes 0.9% (w/v) to 11% (w/v). As used herein, unless the context clearly dictates otherwise, the use of a numerical range expressly includes all possible subranges, all individual values within that range, including integers within such ranges and fractions of such values.

除非另有指示，否則在一系列元件之前的術語「至少」應理解為指該系列中的每個元件。熟習此項技術者將認識到或能夠僅使用例行實驗確定本文所描述的發明之特定實施例之許多等效項。此種等效項意欲由本發明涵蓋。Unless otherwise indicated, the term "at least" preceding a series of elements should be understood to refer to each element of the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be covered by the present invention.

如本文所用，術語「包含(comprises、comprising)」、「包括(includes、including)」、「具有(has、having)」、「含有(contains或containing)」或其任何其他變化形式將理解為意指包含所述整數或整數組但不排除任何其他整數或整數組且意欲係非排他性或開放式的。例如，包含要素清單之組合物、混合物、製程、方法、物件或設備不一定僅限於此等要素，但可包括沒有明確列出或此種組合物、混合物、製程、方法、物件或設備所固有之其他要素。此外，除非相反地明確規定，否則「或」係指包容性或而不是指排他性或。例如，以下中之任一者滿足條件A或B：A係真實(或存在)且B係錯誤的(或不存在)，A係錯誤的(或不存在)且B係真實(或存在)，及A及B均係真實(或存在)。As used herein, the terms "comprises, comprising", "includes, including", "has, having", "contains or containing" or any other variation thereof will be understood to mean It is meant to include the stated integer or group of integers but not to exclude any other integer or group of integers and is intended to be non-exclusive or open ended. For example, a composition, mixture, process, method, article or device comprising a list of elements is not necessarily limited to those elements, but may include those not expressly listed or inherent to such composition, mixture, process, method, article or device other elements. Further, unless expressly stated to the contrary, "or" refers to an inclusive or and not an exclusive or. For example, either of the following satisfies condition A or B: A is true (or present) and B is false (or absent), A is false (or absent) and B is true (or present), and both A and B are real (or exist).

亦應理解，本文所使用的術語「約」、「近似」、「大體上」、「實質上」及類似術語在提及較佳發明之組件之尺寸或特性時指示所描述的尺寸/特性不是嚴格邊界或參數且不排除其功能上相同或類似的微小變化，如具有一般技術者將所理解。至少地，包括數值參數的此類參考將包括使用此項技術中可接受的數學及工業原則(例如四舍五入、測量或其他系統誤差、製造公差等)將不會改變最小有效位的變化。It should also be understood that the terms "about," "approximately," "substantially," "substantially," and similar terms used herein when referring to dimensions or characteristics of components of the preferred invention indicate that the dimensions/characteristics being described are not Strict boundaries or parameters do not exclude minor variations that are functionally identical or similar, as would be understood by those of ordinary skill. At a minimum, such references including numerical parameters will include variations that will not alter the least significant digit using mathematical and industry principles accepted in the art (eg, rounding, measurement or other systematic errors, manufacturing tolerances, etc.).

如本文所使用，術語「免疫遺傳生物標記」或「生物標記」一般係指分子，包括基因、蛋白質、碳水化合物結構或糖脂，其於哺乳動物組織或細胞中或上的表現或分泌可藉由已知方法(或本文所揭示的方法)或一或多個此類分子之性質偵測，且係預測性的或可用於預測(或幫助預測)哺乳動物細胞或組織對治療方案之敏感性且在一些實施例中預測(或幫助預測)個體對治療方案之反應性。在一些實施例中，生物標記包括基因之功能多樣性分數，諸如HLA演化多樣性(HED)分數。免疫遺傳生物標記與保護以免病毒抑制治療之後病毒學/臨床復發之初發及/或持續臨床反應相關聯。本文所揭示的生物標記係基因、蛋白質及/或分數，其存在與中止病毒抑制治療(諸如肝病(例如慢性B型肝炎感染)的NUC治療)之後沒有復發或持續臨床反應相關聯。As used herein, the term "immunogenetic biomarker" or "biomarker" generally refers to a molecule, including a gene, protein, carbohydrate structure, or glycolipid, the expression or secretion of in or on a mammalian tissue or cell can be derived from Detected by known methods (or methods disclosed herein) or properties of one or more such molecules, and are predictive or can be used to predict (or help predict) the sensitivity of mammalian cells or tissues to treatment regimens And in some embodiments predict (or help predict) an individual's responsiveness to a treatment regimen. In some embodiments, the biomarkers include functional diversity scores of genes, such as HLA evolutionary diversity (HED) scores. Immunogenetic biomarkers are associated with protection from initial and/or sustained clinical response to virological/clinical relapse following viral suppressive therapy. The biomarkers disclosed herein are genes, proteins, and/or fractions whose presence correlates with no recurrence or sustained clinical response after discontinuation of viral suppressive therapy, such as NUC therapy for liver disease (eg, chronic hepatitis B infection).

如本文所使用，「人類白血球抗原」或「HLA」係指由人類中主要組織相容性複合物(MHC)基因複合物編碼的一組相關蛋白質。對應於MHC I類 (A、B及C)之HLA從細胞內部呈遞肽。此等肽係由在蛋白酶體中分解的消化蛋白質產生。由MHC I類呈遞的外來抗原吸引破壞細胞的細胞毒性T細胞。對應於MHC II類(DP、DM、DO、DQ及DR)之HLA將抗原從細胞外部呈遞至T淋巴細胞。細胞外蛋白質經胞吞，在蛋白酶體中消化，且將所得抗原決定基肽片段在其遷移至細胞表面之前負載至MHC II類分子上。此等特定抗原刺激T輔助細胞的倍增，此進而刺激產生抗體的B細胞以產生針對該特異性抗原之抗體。As used herein, "human leukocyte antigen" or "HLA" refers to a group of related proteins encoded by the major histocompatibility complex (MHC) gene complex in humans. HLAs corresponding to MHC class I (A, B and C) present peptides from inside the cell. These peptides are produced from digested proteins that are broken down in the proteasome. Foreign antigens presented by MHC class I attract cell-destroying cytotoxic T cells. HLAs corresponding to MHC class II (DP, DM, DO, DQ and DR) present antigens to T lymphocytes from the outside of the cell. Extracellular proteins are endocytosed, digested in the proteasome, and the resulting epitope peptide fragments are loaded onto MHC class II molecules before they migrate to the cell surface. These specific antigens stimulate the multiplication of T helper cells, which in turn stimulate antibody-producing B cells to produce antibodies against the specific antigen.

如本文所使用，「HLA演化多樣性分數」、「HLA演化發散度分數」或「HED分數」意欲遵循其尋常含義，例如，如Pierini及Lenz，Mol.Biol.，Evol.2018，35(9):2145-2158中所描述。其係指一種對胺基酸組成之預測影響(藉由Grantham距離估算)考慮在內的量度，已針對各患者導出作為每個基因分別跨所有HLA I類及II類基因的平均HED。HED分數係定量的，且可跨HLA區域或在HLA區域內對各個體進行計算。As used herein, "HLA Evolutionary Diversity Score", "HLA Evolutionary Divergence Score" or "HED Score" are intended to follow their ordinary meanings, eg, as in Pierini and Lenz, Mol. Biol., Evol. 2018, 35 (9 ): described in 2145-2158. It refers to a measure that takes into account the predicted effect on amino acid composition (estimated by Grantham distance), which has been derived for each patient as the mean HED for each gene across all HLA class I and class II genes, respectively. HED scores are quantitative and can be calculated for each individual across or within an HLA region.

如本文所用，「探針」係指能夠選擇性結合至所欲靶生物分子之任何分子或試劑。該靶分子可為生物標記，例如由生物標記編碼或對應於生物標記的核苷酸轉錄本或蛋白質。有鑑於本揭示，探針可由熟習此項技術者合成，或衍生自適宜生物製劑。探針可專門設計成經標記。可用作探針的分子之實例包括但不限於RNA、DNA、蛋白質、肽、抗體、適體、親和體(affibody)及有機分子。As used herein, "probe" refers to any molecule or reagent capable of selectively binding to a desired target biomolecule. The target molecule may be a biomarker, eg, a nucleotide transcript or protein encoded by or corresponding to the biomarker. Probes can be synthesized by those skilled in the art in view of the present disclosure, or derived from suitable biological agents. Probes can be specially designed to be labeled. Examples of molecules that can be used as probes include, but are not limited to, RNA, DNA, proteins, peptides, antibodies, aptamers, affibodies, and organic molecules.

如本文所用，個體中基因之「基線基因表現」係指在治療個體的肝病之前該個體中基因之基因表現量。As used herein, "baseline gene expression" of a gene in an individual refers to the amount of gene expression of a gene in an individual prior to treatment of the individual for liver disease.

如本文所用，「個體」意指任何動物，較佳係哺乳動物，最佳係人類。如本文所用，術語「哺乳動物」涵蓋任何哺乳動物。哺乳動物之實例包括但不限於牛、馬、羊、豬、貓、狗、小鼠、大鼠、兔、天竺鼠、猴、人類等，更佳係人類。As used herein, "individual" means any animal, preferably a mammal, and most preferably a human. As used herein, the term "mammal" encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.

如本文所用，「樣本」意欲包括其中可偵測到生物標記之表現的細胞、組織或體液的任何樣本採集。此等樣本之實例包括但不限於活檢、抹片、血液、淋巴、尿液、唾液或其任何其他體內分泌或衍生物。血液可例如包括全血、血漿、血清或血液之任何衍生物。樣本可藉由熟習此項技術者已知的各種技術從個體獲得。As used herein, "sample" is intended to include any sample collection of cells, tissues or bodily fluids in which the expression of a biomarker can be detected. Examples of such samples include, but are not limited to, biopsies, smears, blood, lymph, urine, saliva, or any other body endocrine or derivative thereof. Blood can include, for example, whole blood, plasma, serum or any derivative of blood. Samples can be obtained from individuals by various techniques known to those skilled in the art.

如本文所用，「治療」係指治療性治療及預防性(prophylactic/preventative)措施，其中目標係預防或減慢(減輕)靶向病理病症或疾患。彼等需要治療者包括彼等經診斷患有該疾患者以及彼等容易患有該疾患者(例如遺傳學傾向性)或彼等意欲預防該疾患者。As used herein, "treatment" refers to both therapeutic treatment and prophylactic/preventative measures, wherein the goal is to prevent or slow down (lessen) a targeted pathological condition or disorder. Those in need of treatment include those who have been diagnosed with the disease as well as those who are predisposed to the disease (eg, genetic predisposition) or those who wish to prevent the disease.

「單核苷酸多型性」或「SNP」係指RNA或DNA分子(例如多核苷酸)中的單鹼基位置，於該單鹼基位置處，不同對偶基因或替代核苷酸以群體存在。SNP位置(本文中可互換地稱為SNP、SNP位點、SNP基因座)通常在對偶基因之高度保守序列(例如群體之小於1/100或1/1000個成員中不同的序列)之前及之後。個體的各SNP位置的對偶基因可為同合子或雜合子。"Single Nucleotide Polymorphism" or "SNP" refers to a single base position in an RNA or DNA molecule (eg, a polynucleotide) at which a population of different paired genes or surrogate nucleotides exist. SNP positions (referred to interchangeably herein as SNPs, SNP sites, SNP loci) typically precede and follow highly conserved sequences of counterpart genes (eg, sequences that differ in less than 1/100 or 1/1000 members of a population) . The counterpart gene for each SNP position in an individual can be homozygous or heterozygous.

在多型性基因座處存在兩個、三個或四個替代核苷酸序列之情況下，各核苷酸序列稱為「多型性變體」或「核酸變體」。在存在兩個多型性變體之情況下，例如，在來自群體之少數樣本中代表之多型性變體有時稱為「次要對偶基因」且更為普遍代表之多型性變體有時稱為「主要對偶基因」。很多生物體具有各染色體之複本(例如人類)，且彼等具有兩個主要對偶基因或兩個次要對偶基因之個體經常稱為相對於多型性為「同合子」，及彼等具有一個主要對偶基因及一個次要對偶基因之個體通常稱為相對於多型性為「雜合子」。與相對於另一對偶基因為雜合子或同合子之個體相比，相對於一個對偶基因為同合子之個體有時易於變成不同表型。Where two, three or four alternative nucleotide sequences are present at a polymorphic locus, each nucleotide sequence is referred to as a "polymorphic variant" or "nucleic acid variant." In the presence of two polymorphic variants, for example, the polymorphic variant that is represented in a minority of samples from the population is sometimes referred to as the "minor dual gene" and the polymorphic variant that is more commonly represented Sometimes called the "major dual gene". Many organisms have copies of each chromosome (e.g. humans), and individuals who have two major dual genes or two minor dual genes are often referred to as "homozygous" with respect to polymorphism, and they have one Individuals with a major allele and one minor allogeneic allele are often referred to as "heterozygotes" with respect to polymorphism. Individuals who are homozygous with respect to one paired gene are sometimes prone to become phenotyped differently than individuals who are heterozygous or homozygous with respect to the other paired gene.

在識別一或多個免疫遺傳生物標記的遺傳分析中，來自在相關表型中具有不同值之個體之樣本通常係經對偶基因分型及/或基因分型。如本文所用，術語「對偶基因分型」係指用於測定來自病例及對照之組併DNA樣本中多型性變體之對偶基因頻率的過程。藉由將來自各組之DNA組併，計算各組中各基因座之對偶基因頻率。然後將此等對偶基因頻率彼此比較。In a genetic analysis to identify one or more immunogenetic biomarkers, samples from individuals with different values in related phenotypes are often pair-genotyped and/or genotyped. As used herein, the term "dual genotyping" refers to a process for determining the dual gene frequency of polymorphic variants in a cohort of cases and controls and in DNA samples. By pooling the DNA from each group, the dual gene frequency for each locus in each group was calculated. These dual gene frequencies are then compared to each other.

術語「連鎖不平衡」或「LD」係指對偶基因(例如替代核苷酸)在兩個或更多個不同SNP位點處以高於將從給定群體中各對偶基因出現之獨立頻率所期望之頻率的共遺傳。獨立遺傳之兩個對偶基因之共出現之預期頻率係第一對偶基因之頻率乘以第二對偶基因之頻率。以預期頻率共出現之對偶基因稱為呈「連鎖平衡」。相反地，LD係指兩個或更多個不同SNP位點處對偶基因之間的任何非隨機遺傳學關聯，此一般係歸因於兩個基因座沿染色體的物理接近。參見例如U.S. 2008/0299125。The term "linkage disequilibrium" or "LD" refers to a pair of genes (e.g., alternative nucleotides) at two or more different SNP loci at a higher frequency than would be expected from the independent occurrence of each pair of genes in a given population The frequency of co-inheritance. The expected frequency of co-occurrence of two pairs of genes inherited independently is the frequency of the first pair multiplied by the frequency of the second pair. Dual genes that co-occur at the expected frequency are said to be in "linkage equilibrium". Conversely, LD refers to any non-random genetic association between dual genes at two or more different SNP loci, generally due to the physical proximity of the two loci along the chromosome. See, eg, U.S. 2008/0299125.

在一些實施例中，當兩個或更多個SNP位點於給定染色體上彼此親密物理接近時可發生LD且因此在此等SNP位點處之對偶基因將傾向於多代保持不分離，因此在一個SNP位點處的特定核苷酸(對偶基因)將顯示與在位於附近的不同SNP位點處的特定核苷酸(對偶基因)的非隨機關聯。因此，將SNP位點中之一者基因分型將提供與將LD中的另一SNP位點基因分型幾乎相同的資訊。參見例如U.S. 2008/0299125。In some embodiments, LD can occur when two or more SNP loci are in close physical proximity to each other on a given chromosome and thus dual genes at these SNP loci will tend to remain unsegregated for multiple generations, Thus a particular nucleotide at one SNP site (dual gene) will show a non-random association with a particular nucleotide (dual gene) at a different SNP site located nearby. Therefore, genotyping one of the SNP loci will provide nearly the same information as genotyping the other SNP locus in LD. See, eg, U.S. 2008/0299125.

在一些實施例中，為了診斷目的，若發現特定SNP位點可用於診斷，則熟練技術者將認識到具有該SNP位點之LD中的其他SNP位點將亦可用於診斷該病症。在兩個或更多個SNP之間可遇到不同程度之LD，導致一些SNP比其他SNP更親密關聯(亦即處於更強LD)。In some embodiments, if a particular SNP locus is found to be useful for diagnosis for diagnostic purposes, the skilled artisan will recognize that other SNP loci in LDs with that SNP locus will also be useful for diagnosing the disorder. Different degrees of LD can be encountered between two or more SNPs, resulting in some SNPs being more closely related (ie, in stronger LD) than others.

此外，LD沿染色體延伸的物理距離在基因組之不同區域之間有所不同，且因此LD發生所必需的兩個或更多個SNP位點之間的物理分離程度可在基因組之不同區域之間有所不同。參見例如U.S. 2008/0299125。Furthermore, the physical distance that LD extends along a chromosome varies between different regions of the genome, and thus the degree of physical separation between two or more SNP loci necessary for LD to occur can vary between different regions of the genome different. See, eg, U.S. 2008/0299125.

基因型或多型性變體可藉由「單倍型」來表述，該「單倍型」如本文所用係指傾向於一起遺傳的一組DNA變體或多型性。單倍型可指對偶基因之組合或在相同染色體上發現的一組SNP。例如，兩個SNP可存在於各SNP位置包括胞嘧啶變化及腺嘌呤變化的基因內。群體中的某些個體可攜帶一個對偶基因(雜合子)或兩個對偶基因(同合子)，其具有在各SNP位置處具有胞嘧啶之基因。由於該基因中對應於各SNP之兩個胞嘧啶一起行進於此等個體中之一個或兩個對偶基因上，因此該等個體可表徵為相對於該基因中之兩個SNP具有胞嘧啶/胞嘧啶單倍型。A genotypic or polymorphic variant can be expressed by a "haplotype," which as used herein refers to a group of DNA variants or polymorphisms that tend to be inherited together. A haplotype can refer to a combination of paired genes or a group of SNPs found on the same chromosome. For example, two SNPs can be present within a gene where each SNP position includes cytosine changes and adenine changes. Certain individuals in a population may carry one dual gene (heterozygote) or two dual genes (homozygous) with genes that have cytosines at each SNP position. Since the two cytosines in the gene corresponding to each SNP run together on one or both of the paired genes in these individuals, the individuals can be characterized as having cytosine/cytosine relative to the two SNPs in the gene Pyrimidine haplotypes.

術語「胺基酸變化」係指胺基酸序列相對於參考序列之變化(例如一或多個胺基酸之***、取代或缺失，諸如內部缺失或N端或C端截短)。The term "amino acid change" refers to a change in an amino acid sequence relative to a reference sequence (eg, insertion, substitution or deletion of one or more amino acids, such as internal deletions or N- or C-terminal truncations).

術語「變化」係指核苷酸變化或胺基酸變化。The term "change" refers to a nucleotide change or an amino acid change.

術語「陣列」或「微陣列」係指基板上可雜交之陣列元件(較佳多核苷酸探針，例如寡核苷酸)的有序配置。基板可為固體基板(諸如載玻片)或半固體基板(諸如硝化纖維素膜)。The term "array" or "microarray" refers to an ordered arrangement of hybridizable array elements, preferably polynucleotide probes, eg, oligonucleotides, on a substrate. The substrate can be a solid substrate such as a glass slide or a semi-solid substrate such as a nitrocellulose membrane.

術語「投與」就本發明之方法而言意指用於治療性或預防性預防、治療或改善如本文所描述的症候群、疾患或疾病之方法。此類方法包括在療法過程期間的不同時間或以組合形式同時地投與有效量之該治療劑。本發明之方法應理解為涵蓋所有已知治療性治療方案。The term "administering" with respect to the methods of the present invention means a method for the therapeutic or prophylactic prevention, treatment or amelioration of a syndrome, disorder or disease as described herein. Such methods include the simultaneous administration of an effective amount of the therapeutic agent at different times during the course of therapy or in combination. The methods of the present invention should be understood to encompass all known therapeutic treatment regimens.

術語「有效量」意指引起組織系統、動物或人類中生物或醫學反應的活性化合物或藥劑之量，其係為研究人員、獸醫、醫生或其他臨床醫生正在尋找的，其包括預防、治療或改善所治療的症候群、疾患或疾病、或所治療的症候群、疾患或疾病(例如CHB)之症狀。The term "effective amount" means the amount of an active compound or agent that elicits a biological or medical response in a tissue system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician, including prophylactic, therapeutic or Ameliorating the syndrome, disorder or disease being treated, or the symptoms of the syndrome, disorder or disease being treated (eg CHB).

術語「病毒抑制劑」或「病毒抑制治療」係根據其在本領域中之尋常含義且包括抑制病毒(更特別是B型肝炎病毒(HBV))之活性的任何試劑。病毒抑制劑之實例包括但不限於核苷酸或核苷類似物(NUC)，諸如恩替卡韋(Baraclude)、替諾福韋(Viread)、拉米夫定(Epivir)、阿德福韋(Hepsera)及替比夫定(Tyzeka)。The term "viral inhibitor" or "viral inhibitory therapy" is according to its ordinary meaning in the art and includes any agent that inhibits the activity of a virus, more particularly hepatitis B virus (HBV). Examples of viral inhibitors include, but are not limited to, nucleotide or nucleoside analogs (NUCs) such as entecavir (Baraclude), tenofovir (Viread), lamivudine (Epivir), adefovir (Hepsera) and telbivudine (Tyzeka).

術語「非NUC治療」包括使用非NUC藥劑的治療、使用NUC藥劑及其他藥劑之組合的治療、以及停止治療。 CHB 的治療 The term "non-NUC treatment" includes treatment with non-NUC agents, treatment with a combination of NUC agents and other agents, and discontinuation of treatment. Treatment of CHB

HBsAg的清除(血清轉化成HBs抗體(抗HB))係治癒之最接近的相關性及CHB療法之最終目標。CHB治療包括免疫調節劑及病毒抑制劑(諸如NUC)。免疫調節劑之實例包括但不限於IFN-α、Peg-IFN-α、胸腺素-α1及氧化苦參鹼。干擾素(IFN)係藉由抑制病毒DNA合成及增強針對感染HBV之肝細胞之細胞免疫反應來干擾宿主細胞中病毒複製的細胞介素。一般而言，干擾素(IFN)療法具有有限治療持續時間且更有可能產生持續病毒學反應。然而，其使用受到高成本及許多相關副作用的限制。Clearance of HBsAg (seroconversion to HBs antibodies (anti-HB)) is the closest correlator of cure and the ultimate goal of CHB therapy. CHB therapy includes immunomodulators and viral inhibitors such as NUC. Examples of immunomodulatory agents include, but are not limited to, IFN-α, Peg-IFN-α, thymosin-α1, and oxymatrine. Interferons (IFNs) are cytokines that interfere with viral replication in host cells by inhibiting viral DNA synthesis and enhancing cellular immune responses against HBV-infected hepatocytes. In general, interferon (IFN) therapy has a limited duration of treatment and is more likely to produce a sustained virological response. However, its use is limited by high cost and many associated side effects.

NUC之實例包括但不限於替諾福韋、恩替卡韋、拉米夫定、阿德福韋及替比夫定。慢性B型肝炎(CHB)之NUC療法(NA)之目標係以持續方式抑制B型肝炎病毒(HBV)複製，從而預防疾病進展至失償型肝硬化及肝細胞癌(HCC)。總體而言，所有NA在寬廣範圍之患有CHB的人(包括彼等患有失償型肝硬化及移植接受者)中具有極佳安全特性。實際上，全球超過90%的患有CHB的患者目前經口服NUC治療。然而，NUC不會根除HBV，因為其不會影響HBV cccDNA，其充當病毒持續性之持續來源，因此，需要用NUC進行長期治療以維持病毒學控制。Examples of NUCs include, but are not limited to, tenofovir, entecavir, lamivudine, adefovir, and telbivudine. The goal of NUC therapy (NA) for chronic hepatitis B (CHB) is to inhibit hepatitis B virus (HBV) replication in a sustained manner, thereby preventing disease progression to decompensated cirrhosis and hepatocellular carcinoma (HCC). Overall, all NAs have an excellent safety profile in a wide range of people with CHB, including those with decompensated cirrhosis and transplant recipients. In fact, more than 90% of patients with CHB worldwide are currently treated with oral NUC. However, NUC will not eradicate HBV because it does not affect HBV cccDNA, which acts as a persistent source of viral persistence, therefore, long-term treatment with NUC is required to maintain virological control.

為避免終生NUC治療，一直在臨床試驗中評估新策略，包括切換至Peg-IFN或添加於Peg-IFN上、與口服免疫調節劑組合及根據HbsAg量在選定HBeAg陰性患者中中止。 CHB 的病毒抑制治療後的復發 To avoid lifelong NUC treatment, new strategies have been evaluated in clinical trials, including switching to or adding to Peg-IFN, combination with oral immunomodulators, and discontinuation in selected HBeAg-negative patients based on HbsAg volume. Relapse after viral suppressive therapy for CHB

病毒抑制治療之持續時間要求達成至少一次完全病毒學抑制。雖然HBsAg的喪失係與持續治療結束(off-treatment)病毒學抑制相關之理想終點，但HBsAg在抗病毒療法後僅於少數CHB患者中清除。HBeAg喪失及/或血清轉化已廣泛用作CHB療法之替代終點，且幾項實務指南表明當患者達成HBV DNA ＜ 1000 IU/mL，更特別是HBV DNA ＜ 60 IU/mL，更特別是HBV DNA ＜ 1000 IU/mL且ALT ＜ 80 IU/L，更特別是HBV DNA ＜ 60 IU/mL且ALT ＜ 80 IU/L，更特別是HBV DNA ＜ 1000 IU/mL且血清HBsAg ＜ 100 IU/mL，更特別是HBV DNA ＜ 60 IU/mL且HBsAg ＜ 100 IU/mL時，可停止HBV DCC (諸如NUC治療)。然而，約25%至50%的患者仍可在停止抗病毒療法後發展出復發，即使遵循此等建議。Duration of virological suppression therapy required at least one complete virological suppression. Although loss of HBsAg is an ideal endpoint associated with sustained off-treatment virological suppression, HBsAg is cleared in only a minority of CHB patients after antiviral therapy. Loss of HBeAg and/or seroconversion has been widely used as a surrogate endpoint for CHB therapy, and several practice guidelines suggest that when patients achieve HBV DNA < 1000 IU/mL, more particularly HBV DNA < 60 IU/mL, more particularly HBV DNA < 1000 IU/mL and ALT < 80 IU/L, more particularly HBV DNA < 60 IU/mL and ALT < 80 IU/L, more particularly HBV DNA < 1000 IU/mL and serum HBsAg < 100 IU/mL, More particularly, HBV DCC (such as NUC therapy) can be discontinued when HBV DNA < 60 IU/mL and HBsAg < 100 IU/mL. However, approximately 25% to 50% of patients can still develop relapse after stopping antiviral therapy, even when these recommendations are followed.

肝炎復發涉及丙胺酸轉胺酶(ALT)量或HBV DNA量以及HBeAg量的短暫異常。肝炎復發可表徵為病毒學復發、生物醫學復發或臨床復發。目前，使用與開始療法之指南相同的限制，HBV DNA量≥2000 IU/mL或HBeAg陽性可視為病毒學復發。生化復發定義為ALT量升高＞1倍(1x)，正常上限(ULN)的1.5x或2x，取決於研究標準。目前的血清ALT上限雖然因實驗室而異，但一般為約40 IU/L。在一些研究中，使用術語臨床復發，該術語考慮病毒學及生化復發兩組。在一些研究中，如果在治療停止之後的整個隨訪期期間沒有發生臨床及病毒學復發，則患者表示為持續臨床反應者。 用於預測 CHB 的病毒抑制治療後復發或持續臨床反應之免疫遺傳生物標記 Hepatitis recurrence involves transient abnormalities in the amount of alanine transaminase (ALT) or HBV DNA and HBeAg. Hepatitis relapse can be characterized as virological relapse, biomedical relapse, or clinical relapse. Currently, HBV DNA levels ≥2000 IU/mL or HBeAg positivity are considered virological relapse, using the same limitations as guidelines for initiating therapy. Biochemical recurrence was defined as a >1-fold (1x) increase in ALT levels, 1.5x or 2x the upper limit of normal (ULN), depending on study criteria. The current upper limit of serum ALT, although laboratory-specific, is generally about 40 IU/L. In some studies, the term clinical recurrence was used, which considered both virological and biochemical recurrences. In some studies, patients were described as sustained clinical responders if no clinical and virological relapse occurred throughout the follow-up period after treatment was discontinued. Immunogenetic biomarkers for predicting relapse or sustained clinical response after viral suppression therapy in CHB

本發明大體上係關於預測經診斷患有CHB的個體中治療後復發或持續臨床反應，且提供可用於此目的之方法、試劑及套組。本文提供指示及/或預測治療後復發或持續臨床反應之免疫遺傳生物標記。在某些實施例中，該治療係病毒抑制治療，諸如NUC治療。在某些實施例中，復發或持續臨床反應的預測係在CHB的治療之前、期間或之後進行。The present invention generally relates to predicting relapse or sustained clinical response to treatment in individuals diagnosed with CHB, and provides methods, reagents and kits useful for this purpose. Provided herein are immunogenetic biomarkers that indicate and/or predict relapse or sustained clinical response after treatment. In certain embodiments, the treatment is a viral suppressive treatment, such as NUC treatment. In certain embodiments, prediction of relapse or sustained clinical response is performed before, during, or after treatment of CHB.

在某些實施例中，本發明提供CHB感染之病毒控制之免疫遺傳生物標記，用於預測經診斷患有CHB的個體中病毒抑制治療中止之後的復發。根據本發明之實施例，免疫遺傳生物標記中之一者或更多者之存在與此類復發之發生存在負面關聯。In certain embodiments, the present invention provides immunogenetic biomarkers of viral control of CHB infection for use in predicting relapse following discontinuation of viral suppressive therapy in individuals diagnosed with CHB. According to embodiments of the present invention, the presence of one or more of the immunogenetic biomarkers is negatively correlated with the occurrence of such relapses.

在某些實施例中，本發明提供CHB感染之病毒控制之免疫遺傳生物標記，用於預測經診斷患有CHB的個體中病毒抑制治療中止之後的持續臨床反應。根據本發明之實施例，免疫遺傳生物標記中之一者或更多者之存在與此類持續臨床反應之發生存在正面關聯。In certain embodiments, the present invention provides immunogenetic biomarkers of viral control of CHB infection for use in predicting sustained clinical response following discontinuation of viral suppressive therapy in individuals diagnosed with CHB. According to embodiments of the present invention, the presence of one or more of the immunogenetic biomarkers is positively correlated with the occurrence of such sustained clinical responses.

亦提供根據本發明使用的套組、晶片、裝置或檢定。此類檢定、晶片、裝置或套組可包含複數種引子或探針以偵測本文所描述的CHB感染之病毒控制之免疫遺傳生物標記中之一者或多者。此類套組、晶片、裝置可包括個體可在無需健康照護提供者幫助下使用以獲得例如口頰細胞或血液之樣本的儀器及說明書。Kits, wafers, devices or assays for use in accordance with the present invention are also provided. Such assays, chips, devices or kits can include primers or probes to detect one or more of the immunogenetic biomarkers of viral control of CHB infection described herein. Such kits, wafers, devices can include instruments and instructions that an individual can use without the assistance of a health care provider to obtain samples such as buccal cells or blood.

在一些實施例中，本發明提供包含引子及引子對之組合物及套組，其允許本發明之多核苷酸或其任何特定部分及選擇性或特異性地與本發明之核酸分子或其任何部分雜交之探針之特異性擴增。探針可用可偵測之標記(諸如例如放射性同位素、螢光化合物、生物發光化合物、化學發光化合物、金屬螯合劑或酵素)標記。此類探針及引子可用於偵測樣本中多核苷酸的存在且用作用於偵測由多核苷酸編碼之細胞表現蛋白質的構件。如熟練技術者將理解，許多不同引子及探針可基於本文所提供的序列加以製備且可有效用於擴增、選殖及/或判定所關注的免疫遺傳生物標記的存在。In some embodiments, the present invention provides compositions and sets comprising primers and primer pairs that allow the polynucleotides of the present invention, or any particular portion thereof, to interact selectively or specifically with the nucleic acid molecules of the present invention, or any thereof Specific amplification of partially hybridized probes. Probes can be labeled with detectable labels such as, for example, radioisotopes, fluorescent compounds, bioluminescent compounds, chemiluminescent compounds, metal chelators, or enzymes. Such probes and primers can be used to detect the presence of polynucleotides in a sample and as building blocks for detecting cell-expressed proteins encoded by the polynucleotides. As the skilled artisan will appreciate, many different primers and probes can be prepared based on the sequences provided herein and can be effectively used to amplify, clone, and/or determine the presence of an immunogenetic biomarker of interest.

本申請案亦涵蓋開發電腦算法，該算法將從測定免疫遺傳生物標記產生的測試結果轉化為輸出，例如分數，該輸出將用於判定個體在CHB的治療後是否可能具有復發或持續臨床反應。This application also covers the development of computer algorithms that convert test results generated from the determination of immune genetic biomarkers into outputs, such as scores, that will be used to determine whether an individual is likely to have a relapse or sustained clinical response following treatment for CHB.

在一個一般態樣中，提供CHB感染之病毒控制之一組免疫遺傳生物標記，用於判定患有慢性B型肝炎(CHB)感染的個體在病毒抑制治療中止之後是否具有高或低復發機率。In one general aspect, a panel of immunogenetic biomarkers for viral control of CHB infection is provided for use in determining whether individuals with chronic hepatitis B (CHB) infection have a high or low chance of relapse after cessation of viral suppressive therapy.

根據本發明，該組免疫遺傳生物標記能夠識別在CHB的治療之後具有不同肝炎復發風險的患者之子組，此在許多方面可為有益的，包括降低將患者暴露於無效治療，達成較高反應率，及用替代療法治療預測患者以避免或最小化可能復發之能力。生物標記可另外用於其他目的，諸如用於在臨床試驗中將患者分層，在概念證明試驗中藉由排除子群體來減小樣本尺寸，及臨床試驗中之平衡治療臂。According to the present invention, the panel of immunogenetic biomarkers enables the identification of subgroups of patients with different risks of hepatitis recurrence following treatment of CHB, which may be beneficial in a number of ways, including reducing exposure of patients to ineffective treatments, achieving higher response rates , and treatment with alternative therapy predicts the ability of patients to avoid or minimize possible relapse. Biomarkers can additionally be used for other purposes, such as for stratifying patients in clinical trials, reducing sample size by excluding subpopulations in proof-of-concept trials, and balancing treatment arms in clinical trials.

較佳地，該等免疫遺傳生物標記係選自由以下組成之群： i. 人類白血球抗原(HLA)對偶基因； ii. 一或多個HLA-C單核苷酸多型性(SNP)； iii. HLA演化多樣性(HED)分數；及 iv. 白血球受體複合物(LCR) SNP； 該組免疫遺傳生物標記可包含1、2、3或4種類型之本文所描述之免疫遺傳生物標記。較佳地，該組免疫遺傳生物標記用於判定患有慢性B型肝炎(CHB)感染的個體在病毒抑制治療中止之後兩年時期之內是否具有高或低復發機率。 Preferably, the immunogenetic biomarkers are selected from the group consisting of: i. Human leukocyte antigen (HLA) pair genes; ii. One or more HLA-C single nucleotide polytypes (SNPs); iii. HLA Evolutionary Diversity (HED) score; and iv. Leukocyte receptor complex (LCR) SNPs; The panel of immunogenetic biomarkers can comprise 1, 2, 3 or 4 types of immunogenetic biomarkers described herein. Preferably, the panel of immunogenetic biomarkers is used to determine whether an individual with chronic hepatitis B (CHB) infection has a high or low chance of relapse within a two-year period following cessation of viral suppressive therapy.

在某些實施例中，復發機率的預測係在CHB的病毒抑制治療之前、期間或之後進行。In certain embodiments, prediction of relapse probability is performed before, during, or after viral suppressive therapy for CHB.

在某些實施例中，免疫遺傳生物標記包含HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在。HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在預測病毒抑制治療中止之後復發的低機率，較佳係病毒學復發的低機率。HLA對偶基因B*51或C*15的不存在或HLA對偶基因C*07的存在預測病毒抑制治療中止之後復發的高機率，較佳係病毒學復發的高機率。在其他實施例中，HLA對偶基因C*15係C*15:02及HLA對偶基因C*07係C*07:02。In certain embodiments, the immunogenetic biomarker comprises the presence of HLA counterpart B*51 or C*15 or the absence of HLA counterpart C*07. The presence of the HLA counterpart B*51 or C*15 or the absence of the HLA counterpart C*07 predicts a low chance of relapse after cessation of viral suppressive therapy, preferably a low chance of virological relapse. The absence of the HLA counterpart B*51 or C*15 or the presence of the HLA counterpart C*07 predicts a high probability of relapse, preferably virological relapse, after cessation of viral suppressive therapy. In other embodiments, the HLA counterpart C*15 is C*15:02 and the HLA counterpart C*07 is C*07:02.

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之HLA-C SNP：rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、rs9264039及rs3868078或其互補序列。本文所描述的HLA-C SNP的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的HLA-C SNP的不存在預測在病毒抑制治療中止之後復發的高機率。In certain embodiments, the immunogenetic biomarker comprises an HLA-C SNP selected from the group consisting of: rs2394952, rs3130542, rs2894202, rs9264523, rs1049281, rs9264643, rs1130838, rs2394888, AX-83089411, rs2308622, rs91640416, rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、 rs9264039 and rs3868078 or their complements. The presence of the HLA-C SNPs described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the HLA-C SNPs described herein predicts a high probability of relapse following discontinuation of viral suppressive therapy.

在其他實施例中，HLA-C SNP係選自由以下組成之群： rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750或其互補序列。本文所描述的HLC-C SNP可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。在其他實施例中，HLA-C SNP係選自由以下組成之群： rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、 rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750或其互補序列。 The HLC-C SNPs described herein can be used to predict the probability of virological relapse following discontinuation of virological suppression therapy for CHB.

在其他實施例中，HLA-C SNP係選自由s4084090、rs9264127、rs9264039及rs3868078或其互補序列組成之群。本文所描述的HLC-C SNP可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。In other embodiments, the HLA-C SNPs are selected from the group consisting of s4084090, rs9264127, rs9264039 and rs3868078 or their complements. The HLC-C SNPs described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該免疫遺傳生物標記包含至少一個大於選自下表之臨限值之HED分數： HLA 區域 HLA 基因 變數 臨限值 平均HLA I類 HLA-A HED_HLA_A_CAT_VR 3.88 平均HLA I類 HLA-B HED_HLA_B_CAT_VR 9.37 平均HLA I類 HLA-C HED_HLA_C_CAT_VR 0.00 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_VR 8.69 平均HLA II類 HLA-DPB1 HED_HLA_P_CAT_VR 2.21 平均HLA II類 HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_VR 12.68 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_VR 7.55 平均HLA I類 HLA-A HED_HLA_A_CAT_CR 3.88 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_CR 7.67 平均HLA I類 HLA-C HED_HLA_C_CAT_SCR 7.37 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_SCR 7.61 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_SCR 8.21 In certain embodiments, the immunogenetic biomarker comprises at least one HED score greater than a threshold value selected from the following table: HLA region HLA gene variable Threshold value Average HLA class I HLA-A HED_HLA_A_CAT_VR 3.88 Average HLA class I HLA-B HED_HLA_B_CAT_VR 9.37 Average HLA class I HLA-C HED_HLA_C_CAT_VR 0.00 Average HLA class I MEAN_MHCI HED_MEANI_CAT_VR 8.69 Average HLA class II HLA-DPB1 HED_HLA_P_CAT_VR 2.21 Average HLA class II HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_VR 12.68 Average HLA class II MEAN_MHCII HED_MEANII_CAT_VR 7.55 Average HLA class I HLA-A HED_HLA_A_CAT_CR 3.88 Average HLA class II MEAN_MHCII HED_MEANII_CAT_CR 7.67 Average HLA class I HLA-C HED_HLA_C_CAT_SCR 7.37 Average HLA class I MEAN_MHCI HED_MEANI_CAT_SCR 7.61 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 Average HLA class II MEAN_MHCII HED_MEANII_CAT_SCR 8.21

本文所描述的HED分數的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的HED分數的不存在預測在病毒抑制治療中止之後復發的高機率。The presence of the HED scores described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the HED scores described herein predicts a high chance of relapse after cessation of viral suppressive therapy.

在其他實施例中，HED分數係選自由HED HLA-A大於3.88之值、HED HLA-B大於9.37之值、HED HLA-C大於0.00之值、平均HED HLA I類大於8.69之值、HED HLA-DPB1大於2.21之值、HED HLA-DQB1大於11.98之值、HED HLA-DRB1大於12.68之值及平均HED HLA II類大於7.55之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。In other embodiments, the HED score is selected from the group consisting of HED HLA-A greater than 3.88, HED HLA-B greater than 9.37, HED HLA-C greater than 0.00, average HED HLA class I value greater than 8.69, HED HLA - A group consisting of a value of DPB1 greater than 2.21, a value of HED HLA-DQB1 greater than 11.98, a value of HED HLA-DRB1 greater than 12.68 and a value of average HED HLA class II greater than 7.55. The HED scores described herein can be used to predict the probability of virological relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，HED分數係選自由HED HLA-A大於3.88之值及平均HED HLA II類大於7.67之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。In other embodiments, the HED score is selected from the group consisting of a HED HLA-A value greater than 3.88 and a mean HED HLA class II value greater than 7.67. The HED scores described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，HED分數係選自由HED HLA-C大於7.37之值、平均HED HLA I類大於7.61之值、HED HLA-DRB1大於14.16之值及平均HED HLA II類大於8.21之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後持續臨床反應的機率。In other embodiments, the HED score is selected from the group consisting of HED HLA-C greater than 7.37, mean HED HLA class I greater than 7.61, HED HLA-DRB1 greater than 14.16, and mean HED HLA class II greater than 8.21 group. The HED scores described herein can be used to predict the probability of sustained clinical response after discontinuation of viral suppressive therapy for CHB.

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之LCR SNP：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。本文所描述的LCR SNP的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的LCR SNP的不存在預測在病毒抑制治療中止之後復發的高機率。In certain embodiments, the immunogenetic biomarker comprises an LCR SNP selected from the group consisting of: rs10426302, rs59537494, rs28366008, rs36625, rs635608, rs7595, rs731170, rs28513, rs12459334, rs11666535, rs4806807, rs39084367, rs39084367 rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、 rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、 rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。 The presence of the LCR SNPs described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the LCR SNPs described herein predicts a high probability of relapse following discontinuation of viral suppressive therapy.

在其他實施例中，LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627或且其互補序列。本文所描述的LCR SNP可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。在其他實施例中，LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、 rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、 rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627或且其互補序列。 The LCR SNPs described herein can be used to predict the probability of virological relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，LCR SNP係選自由以下組成之群：rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。本文所描述的LCR SNP可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。在其他實施例中，LCR SNP係選自由以下組成之群：rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、 rs10412569, AX-3232794851, rs622941 and rs60690598 or their complements. The LCR SNPs described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，免疫遺傳生物標記係藉由全基因組分型(GMAS)確定，其中該基因型鑑定(genotype calling)係針對雙對偶基因SNP進行。在某些實施例中，免疫遺傳生物標記係藉由人類白血球抗原(HLA)分型藉由Sanger定序或藉由聚合酶鏈反應-基於序列之分型(PCR-SBT)方法來確定。In certain embodiments, immunogenetic biomarkers are determined by genome-wide genotyping (GMAS), wherein the genotype calling is performed for double paired SNPs. In certain embodiments, immunogenetic biomarkers are determined by human leukocyte antigen (HLA) typing by Sanger sequencing or by polymerase chain reaction-sequence-based typing (PCR-SBT) methods.

在某些實施例中，SNP或對偶基因係藉由選自由以下組成之群之方法來判定：DNA定序、限制片段長度多型性(RFLP分析)、對偶基因特異性寡核苷酸(ASO)分析、變性/溫度梯度凝膠電泳(DGGE/TGGE)、單股構象多型性(SSCP)分析、雙去氧指紋分析(ddF)、焦磷酸定序分析、acycloprime分析、反向墨點轉漬(Reverse dot blot)、基因晶片(GeneChip)微陣列、動態對偶基因特異性雜交(DASH)、肽核酸(PNA)及鎖核酸(LNA)探針、TaqMan、分子信標(Molecular Beacons)、嵌入染料(Intercalating dye)、FRET引子、AlphaScreen、SNPstream、遺傳位元分析(GBA)、多重微定序、SNaPshot、MassEXTEND、MassArray、GOOD檢定、微陣列微定序(Microarray miniseq)、陣列式引子延伸(APEX)、微陣列引子延伸、標籤陣列(Tag array)、經編碼之微球(Coded microsphere)、模板導向併入(TDI)、螢光偏振、比色寡核苷酸連接檢定(OLA)、序列編碼OLA (Sequence-coded OLA)、微陣列連接、連接酶鏈反應、扣鎖(Padlock)探針、滾環擴增(Rolling circle amplification)及侵入物(Invader)檢定。In certain embodiments, the SNP or counterpart is determined by a method selected from the group consisting of DNA sequencing, restriction fragment length polymorphism (RFLP analysis), counterpart-specific oligonucleotides (ASO) ) analysis, denaturing/temperature gradient gel electrophoresis (DGGE/TGGE), single-strand conformational polymorphism (SSCP) analysis, dideoxy fingerprint analysis (ddF), pyrophosphate sequencing analysis, acycloprime analysis, reverse ink dot transfer Reverse dot blot, GeneChip microarray, Dynamic Dual Gene-Specific Hybridization (DASH), Peptide Nucleic Acid (PNA) and Locked Nucleic Acid (LNA) Probes, TaqMan, Molecular Beacons, Embedding Intercalating dye, FRET primers, AlphaScreen, SNPstream, genetic bit analysis (GBA), multiplex microsequencing, SNaPshot, MassEXTEND, MassArray, GOOD assay, Microarray miniseq, array primer extension ( APEX), Microarray Primer Extension, Tag array, Coded microsphere, Template Directed Incorporation (TDI), Fluorescence Polarization, Colorimetric Oligonucleotide Ligation Assay (OLA), Sequence Sequence-coded OLA (Sequence-coded OLA), microarray ligation, ligase chain reaction, Padlock probes, Rolling circle amplification and Invader assays.

根據本申請案之實施例，HED分數係藉由熟習此項技術者已知的任何已知方法來確定。HED分數通常在考慮對胺基酸組成之預測影響下測定且可分別跨所有基因導出。4欄位HLA遺傳密碼可然後用於在比對文檔中將對偶基因與相應蛋白質相匹配。就基因型中各對對偶基因而言，使用Grantham距離度量來衡量其功能距離(就經編碼之蛋白質而言)。就各HLA蛋白基因座而言，MHC抗原識別域之胺基酸座標可使用Ensembl資料庫蛋白質註解來識別(ftp://ftp.ebi.ac.uk/pub/databases/ipd/imgt/hla/alignments/；Robinson等人，Nucleic acids research，2020，48: D948–55；Zerbino等人，Nucleic Acids Research，2018，46: D754–61)。整體而言，座標涵蓋HLA-I型基因中之外顯子2及3及HLA-II型基因中之外顯子2及外顯子1之一部分。對於各個體及HLA基因座，提取使用4欄位HLA對偶基因識別碼的HLA基因型。4欄位HLA遺傳密碼然後用於在比對文檔中將對偶基因與相應蛋白質相匹配。就基因型中各對對偶基因而言，使用Grantham距離度量來衡量其功能距離(就經編碼之蛋白質而言)。Grantham距離係兩個胺基酸之間的定量成對距離。一對的距離考慮其物理化學特性(各胺基酸之生化組成、極性及體積)。一對序列之給定比對之Grantham整體發散度係藉由求和個別胺基酸對距離值且然後藉由將總和除以比對長度來計算(Grantham等人，Science，1974，185: 862–4)。According to embodiments of the present application, the HED score is determined by any known method known to those skilled in the art. HED scores are typically determined taking into account the predicted effect on amino acid composition and can be derived separately across all genes. The 4-column HLA genetic code can then be used to match counterpart genes to corresponding proteins in the alignment file. For each pair of dual genes in the genotype, the Grantham distance metric was used to measure the functional distance (in terms of encoded protein). For each HLA protein locus, the amino acid coordinates of the MHC antigen recognition domain can be identified using Ensembl database protein annotations (ftp://ftp.ebi.ac.uk/pub/databases/ipd/imgt/hla/ alignments/; Robinson et al, Nucleic Acids Research, 2020, 48: D948–55; Zerbino et al, Nucleic Acids Research, 2018, 46: D754–61). In general, the coordinates encompass exons 2 and 3 in HLA-type I genes and a portion of exon 2 and exon 1 in HLA-type II genes. For each individual and HLA locus, HLA genotypes using the 4-column HLA paired gene identification code were extracted. The 4-column HLA genetic code is then used to match the counterpart gene to the corresponding protein in the alignment file. For each pair of dual genes in the genotype, the Grantham distance metric was used to measure the functional distance (in terms of encoded protein). The Grantham distance is the quantitative pairwise distance between two amino acids. The distance of a pair takes into account its physicochemical properties (biochemical composition, polarity and volume of each amino acid). The Grantham global divergence for a given alignment of a pair of sequences is calculated by summing the individual amino acid pair distance values and then by dividing the sum by the alignment length (Grantham et al., Science, 1974, 185:862 –4).

在某些實施例中，本申請案之陣列包含可用於偵測本文所描述的SNP之核酸分子之個體或集合。例如，本申請案之陣列可包含一系列離散放置的個別核酸寡核苷酸或幾組核酸寡核苷酸組合，其可與包含具有靶SNP之核酸之樣本雜交，其中此種雜交指示靶SNP的存在。In certain embodiments, the arrays of the present application comprise individuals or collections of nucleic acid molecules that can be used to detect the SNPs described herein. For example, the arrays of the present application can comprise a series of discretely placed individual nucleic acid oligonucleotides or groups of nucleic acid oligonucleotide combinations that can hybridize to a sample comprising nucleic acid having a target SNP, wherein such hybridization is indicative of the target SNP The presence.

此項技術中熟知用於將核酸附接至固體基板(諸如載玻片)的若干技術。一種方法係將含有能夠附接至固體基板(諸如胺基、胺基之衍生物或具有正電荷之另一基團)的部分之經修飾鹼基或類似物併入至合成的核酸分子中。然後將合成的產物與固體基板(諸如載玻片)接觸，用醛或另一反應基團塗佈該固體基板，該另一反應基團將與位於經擴增產物上的反應基團形成共價連接且變成共價附接至載玻片。其他方法(諸如彼等使用胺基丙基二氧化矽表面化學之方法)亦係此項技術中已知的，如在cmt.corning.com and cmgm.stanford.edu/pbrownl上的全球資訊網上所揭示。Several techniques for attaching nucleic acids to solid substrates, such as glass slides, are well known in the art. One approach is to incorporate modified bases or analogs into synthetic nucleic acid molecules that contain a moiety capable of attaching to a solid substrate, such as an amine group, a derivative of an amine group, or another group with a positive charge. The synthesized product is then contacted with a solid substrate, such as a glass slide, which is coated with an aldehyde or another reactive group that will form a co-polymer with a reactive group located on the amplified product valently linked and became covalently attached to the glass slide. Other methods, such as those using aminopropyl silica surface chemistry, are also known in the art, eg on the World Wide Web at cmt.corning.com and cmgm.stanford.edu/pbrownl revealed.

亦可使用此項技術中已知的方法將基團附接至寡核苷酸，該等寡核苷酸可稍後轉化為反應基團。任何對寡核苷酸之核苷酸之附接將成為寡核苷酸之部分，其可然後附接至微陣列之固體表面。可如所使用的技術所要求及/或允許在附接至固體基板之前或之後進一步修飾經擴增核酸，諸如透過切割成片段或藉由附接可偵測之標記。Groups can also be attached to oligonucleotides, which can later be converted into reactive groups, using methods known in the art. Any nucleotide attachment to the oligonucleotide will become part of the oligonucleotide, which can then be attached to the solid surface of the microarray. The amplified nucleic acid may be further modified, such as by cleavage into fragments or by attaching a detectable label, as required and/or permitted by the technique used, either before or after attachment to the solid substrate.

為用於上文描述或建議之應用中，亦提供套組或製品。此類套組可包括載體構件，該載體構件經區室化以封閉限制地接收一或多個容器構件，諸如小瓶、管及類似者，該容器構件中之各者包括待用於該方法中的獨立元件中之一者。例如，容器構件中之一者可包括偵測到或可偵測到標記之探針。此種探針可為對包含本文所描述的SNP具有特異性之多核苷酸。在套組利用核酸雜交來偵測靶核酸之情況下，該套組亦可具有含有核苷酸以用於靶核酸序列的擴增之容器及/或包括報導子構件之容器，諸如結合至報導子分子(諸如酵素標記、螢光標記或放射性同位素標記)之生物素結合蛋白，諸如抗生物素蛋白或鏈黴親和素。Kits or articles of manufacture are also provided for use in the applications described or suggested above. Such a kit can include a carrier member that is compartmentalized to receive one or more container members, such as vials, tubes, and the like, in a closed confinement, each of the container members comprising to be used in the method one of the independent components of . For example, one of the container members can include a probe that detects or can detect a label. Such probes can be polynucleotides specific for comprising the SNPs described herein. Where the kit utilizes nucleic acid hybridization to detect target nucleic acids, the kit may also have a container containing nucleotides for amplification of the target nucleic acid sequence and/or a container comprising reporter components, such as binding to a reporter Biotin-binding proteins such as avidin or streptavidin of sub-molecules such as enzyme-labeled, fluorescently-labeled or radioisotope-labeled.

套組將通常包括上文所描述的容器及包含從商業及使用者觀點來看所需的材料之一或多個其他容器，該所需材料包括緩衝劑、稀釋劑、過濾器、針、注射器及具有使用說明書之包裝插頁。標籤可存在於容器上以指示將組合物用於特定療法或非治療應用，且亦可指示體內或體外使用的方向，諸如彼等上文所描述者。A kit will generally include the container described above and one or more other containers containing materials required from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes And package insert with instruction manual. Labels may be present on the container to indicate that the composition is to be used for a particular therapeutic or non-therapeutic application, and may also indicate directions for in vivo or in vitro use, such as those described above.

套組中之其他可選組件包括一或多種緩衝劑(例如阻斷緩衝劑、洗滌緩衝劑、基板緩衝劑等)、其他試劑(諸如藉由酵素標記化學改變的基板(例如色原體))、抗原決定基取回溶液、對照樣本(正對照及/或負對照)、對照載玻片等。一種另外組分係酵素，例如，包括但不限於核酸酶、連接酶或聚合酶。Other optional components in the kit include one or more buffers (eg, blocking buffers, wash buffers, substrate buffers, etc.), other reagents (such as by enzymatic labeling of chemically altered substrates (eg, chromogens)) , Epitope retrieval solution, control samples (positive control and/or negative control), control slides, etc. An additional component is an enzyme, for example, including but not limited to nucleases, ligases, or polymerases.

SNP係人類中最常見的遺傳變異類型。各SNP代表單個DNA構築嵌段(稱為核苷酸)的差異。例如，SNP可在某一段DNA中用核苷酸胸腺嘧啶(T)置換核苷酸胞嘧啶(C)。此等變異可為獨特的或發生在許多個體中。最常見的是，此等變異在基因之間的DNA中發現。SNPs are the most common type of genetic variation in humans. Each SNP represents a difference in a single DNA building block (called a nucleotide). For example, a SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a stretch of DNA. Such variations can be unique or occur in many individuals. Most commonly, these variations are found in the DNA between genes.

物種成員之間SNP的遺傳變異的測定稱為SNP基因分型。其係基因分型的一種形式，該基因分型係測定更一般遺傳變異。The determination of genetic variation in SNPs among species members is called SNP genotyping. It is a form of genotyping that measures more general genetic variation.

SNP的遺傳變異可藉由熟習此項技術者已知的任何方法偵測。此類方法包括但不限於DNA定序；引子延伸檢定，包括對偶基因特異性核苷酸併入檢定及對偶基因特異性引子延伸檢定(例如對偶基因特異性PCR、對偶基因特異性連接鏈反應(LCR)及空隙-LCR (gap-LCR))；對偶基因特異性寡核苷酸雜交檢定(例如寡核苷酸連接檢定)；其中使用免受切割試劑影響的保護來偵測核酸雙股中的不匹配鹼基之切割保護檢定；MutS蛋白結合之分析；比較變體及野生型核酸分子之遷移率之電泳分析；變性梯度凝膠電泳(DGGE，如在例如Myers等人 (1985) Nature 313:495中)；在不匹配鹼基對處之RNA酶切割之分析；異源雙股DNA之化學或酶促切割之分析；質譜法(例如MALDI-TOF)；遺傳位元分析(GBA)；5′核酸酶檢定(例如TaqMan®)；及採用分子信標之檢定。下文更詳細地論述某些此等方法。Genetic variation in SNPs can be detected by any method known to those skilled in the art. Such methods include, but are not limited to, DNA sequencing; primer extension assays, including pair-specific nucleotide incorporation assays and pair-specific primer extension assays (eg, pair-specific PCR, pair-specific ligation chain reaction ( LCR) and gap-LCR (gap-LCR); dual gene-specific oligonucleotide hybridization assays (eg, oligonucleotide ligation assays); wherein protection from cleavage reagents is used to detect nucleic acid duplexes Cleavage protection assays for mismatched bases; analysis of MutS protein binding; electrophoretic analysis to compare mobilities of variant and wild-type nucleic acid molecules; denaturing gradient gel electrophoresis (DGGE, as in, eg, Myers et al. (1985) Nature 313: 495); analysis of RNase cleavage at mismatched base pairs; analysis of chemical or enzymatic cleavage of heteroduplex DNA; mass spectrometry (eg MALDI-TOF); genetic bit analysis (GBA); 5 'Nuclease assays (eg TaqMan®); and assays using molecular beacons. Some of these methods are discussed in more detail below.

靶核酸變異的偵測可使用此項技術中熟知的技術藉由分子選殖及靶核酸的定序來達成。或者，可使用擴增技術(諸如聚合酶鏈反應(PCR))直接從來自腫瘤組織之基因組DNA製劑擴增靶核酸序列。可然後判定經擴增序列的核酸序列且由其識別的變異。Detection of target nucleic acid variation can be accomplished by molecular cloning and sequencing of the target nucleic acid using techniques well known in the art. Alternatively, amplification techniques, such as polymerase chain reaction (PCR), can be used to directly amplify target nucleic acid sequences from genomic DNA preparations from tumor tissue. Variations in the nucleic acid sequence of the amplified sequence and identified thereby can then be determined.

亦可藉由不匹配偵測方法來偵測變異。不匹配係並非100%互補的雜交核酸雙股。缺乏完全互補性可由於缺失、***、倒置或取代引起。Variations can also be detected by mismatch detection methods. Mismatched lines are not 100% complementary hybrid nucleic acid duplexes. Lack of perfect complementarity can result from deletions, insertions, inversions or substitutions.

有關SNP的詳細資訊可從單核苷酸多型性數據庫(Single Nucleotide Polymorphism Database；dbSNP)獲得，該數據庫係國家生物技術資訊中心(National Center for Biotechnology Information；NCBI)與美國國家人類基因組研究所( National Human Genome Research Institute；NHGRI)合作開發且託管不同物種之間的遺傳變異之免費公共檔案館。在dbSNP中，SNP係藉由參考SNP ID號(「rs#」)識別。Detailed information on SNPs can be obtained from the Single Nucleotide Polymorphism Database (dbSNP), a database of the National Center for Biotechnology Information (NCBI) and the National Human Genome Research Institute ( The National Human Genome Research Institute; NHGRI) collaborates to develop and host a free public archive of genetic variation between species. In dbSNP, SNPs are identified by reference SNP ID numbers ("rs#").

在另一個一般態樣中，提供一種組合，其用於預測有需要個體中在治療慢性B型肝炎(CHB)感染之病毒抑制之後的低復發風險，該組合包含能夠偵測申請案中所描述的免疫遺傳生物標記中之一者或多者之試劑。In another general aspect, there is provided a combination for predicting a low risk of relapse following viral suppression in the treatment of chronic hepatitis B (CHB) infection in an individual in need thereof, the combination comprising the ability to detect as described in the application A reagent for one or more of the immunogenetic biomarkers.

在某些實施例中，免疫遺傳生物標記的偵測係在病毒抑制治療之前、期間或之後進行。In certain embodiments, detection of immunogenetic biomarkers is performed before, during, or after viral suppressive therapy.

在某些實施例中，該組合進一步包含一或多種用於治療CHB之治療劑。In certain embodiments, the combination further comprises one or more therapeutic agents for the treatment of CHB.

在另一個一般態樣中，提供一種用於血清學HLA分型之套組、或用於遺傳學HLA分型之套組，諸如DNA晶片、PCR套組或一組PCR引子及/或探針，其用於預測病毒抑制劑於治療有需要個體中慢性B型肝炎(CHB)感染之功效。 使用方法 In another general aspect, there is provided a kit for serological HLA typing, or a kit for genetic HLA typing, such as a DNA chip, a PCR kit, or a set of PCR primers and/or probes , which is used to predict the efficacy of viral inhibitors in the treatment of chronic hepatitis B (CHB) infection in individuals in need. Instructions

本文提供使用根據本發明之一個實施例之免疫遺傳生物標記預測有需要個體之慢性B型肝炎(CHB)感染之治療中止之後的復發或持續臨床反應之方法。免疫遺傳生物標記亦可用於其他目的，諸如用於在臨床試驗中將患者分層，在概念證明試驗中藉由排除子群體來減小樣本尺寸，及臨床試驗中之平衡治療臂。Provided herein are methods of predicting relapse or sustained clinical response following discontinuation of treatment of chronic hepatitis B (CHB) infection in an individual in need using immunogenetic biomarkers according to one embodiment of the present invention. Immunogenetic biomarkers can also be used for other purposes, such as for stratifying patients in clinical trials, reducing sample size by excluding subpopulations in proof-of-concept trials, and balancing treatment arms in clinical trials.

在一個一般態樣中，本申請案提供一種判定患有慢性B型肝炎(CHB)感染的個體在病毒抑制治療中止之後是否具有高或低復發機率之方法，該方法包括： a. 偵測從該個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i. 人類白血球抗原(HLA)對偶基因； ii. 一或多個HLA-C單核苷酸多型性(SNP)； iii. HLA演化多樣性(HED)分數；及 iv. 白血球受體複合物(LCR) SNP； b. 若在生物樣本中偵測到一或多個免疫遺傳生物標記，則判定個體之復發機率為低，或若在生物樣本中未偵測到免疫遺傳生物標記，則判定個體之復發機率為高。 In one general aspect, the present application provides a method of determining whether an individual with chronic hepatitis B (CHB) infection has a high or low chance of relapse following discontinuation of viral suppressive therapy, the method comprising: a. Detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. Human leukocyte antigen (HLA) pair genes; ii. One or more HLA-C single nucleotide polytypes (SNPs); iii. HLA Evolutionary Diversity (HED) score; and iv. Leukocyte receptor complex (LCR) SNPs; b. If one or more immunogenetic biomarkers are detected in the biological sample, the probability of recurrence of the individual is determined to be low, or if no immune genetic biomarkers are detected in the biological sample, the probability of recurrence of the individual is determined to be high.

較佳地，該方法包括判定患有慢性B型肝炎(CHB)感染的個體在病毒抑制治療中止之後兩年時期之內是否具有高或低復發機率。Preferably, the method comprises determining whether an individual suffering from chronic hepatitis B (CHB) infection has a high or low chance of relapse within a two-year period following cessation of viral suppressive therapy.

在某些實施例中，復發機率的預測係在CHB的病毒抑制治療之前、期間或之後進行。In certain embodiments, prediction of relapse probability is performed before, during, or after viral suppressive therapy for CHB.

如本文所用，當免疫遺傳生物標記係HED分數時，「偵測從個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在」係指判定生物樣本中之HED分數。As used herein, when the immunogenetic biomarker is the HED score, "detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from an individual" refers to determining the HED score in the biological sample .

在某些實施例中，免疫遺傳生物標記包含HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在。HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在預測病毒抑制治療中止之後復發的低機率，較佳係病毒學復發的低機率。HLA對偶基因B*51或C*15的不存在或HLA對偶基因C*07的存在預測病毒抑制治療中止之後復發的高機率，較佳係病毒學復發的高機率。在其他實施例中，HLA對偶基因C*15係C*15:02及HLA對偶基因C*07係C*07:02。In certain embodiments, the immunogenetic biomarker comprises the presence of HLA counterpart B*51 or C*15 or the absence of HLA counterpart C*07. The presence of the HLA counterpart B*51 or C*15 or the absence of the HLA counterpart C*07 predicts a low chance of relapse after cessation of viral suppressive therapy, preferably a low chance of virological relapse. The absence of the HLA counterpart B*51 or C*15 or the presence of the HLA counterpart C*07 predicts a high probability of relapse, preferably virological relapse, after cessation of viral suppressive therapy. In other embodiments, the HLA counterpart C*15 is C*15:02 and the HLA counterpart C*07 is C*07:02.

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之HLA-C SNP：rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、rs9264039及rs3868078或其互補序列。本文所描述的HLA-C SNP的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的HLA-C SNP的不存在預測在病毒抑制治療中止之後復發的高機率。In certain embodiments, the immunogenetic biomarker comprises an HLA-C SNP selected from the group consisting of: rs2394952, rs3130542, rs2894202, rs9264523, rs1049281, rs9264643, rs1130838, rs2394888, AX-83089411, rs2308622, rs91640416, rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、 rs9264039 and rs3868078 or their complements. The presence of the HLA-C SNPs described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the HLA-C SNPs described herein predicts a high probability of relapse following discontinuation of viral suppressive therapy.

在其他實施例中，HLA-C SNP係選自由以下組成之群： rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750或其互補序列。本文所描述的HLC-C SNP可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。在其他實施例中，HLA-C SNP係選自由以下組成之群： rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、 rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750或其互補序列。 The HLC-C SNPs described herein can be used to predict the probability of virological relapse following discontinuation of virological suppression therapy for CHB.

在其他實施例中，HLA-C SNP係選自由s4084090、rs9264127、rs9264039及rs3868078或其互補序列組成之群。本文所描述的HLC-C SNP可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。In other embodiments, the HLA-C SNPs are selected from the group consisting of s4084090, rs9264127, rs9264039 and rs3868078 or their complements. The HLC-C SNPs described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該免疫遺傳生物標記包含至少一個大於選自下表之臨限值之HED分數： HLA 區域 HLA 基因 變數 臨限值 平均HLA I類 HLA-A HED_HLA_A_CAT_VR 3.88 平均HLA I類 HLA-B HED_HLA_B_CAT_VR 9.37 平均HLA I類 HLA-C HED_HLA_C_CAT_VR 0.00 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_VR 8.69 平均HLA II類 HLA-DPB1 HED_HLA_P_CAT_VR 2.21 平均HLA II類 HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_VR 12.68 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_VR 7.55 平均HLA I類 HLA-A HED_HLA_A_CAT_CR 3.88 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_CR 7.67 平均HLA I類 HLA-C HED_HLA_C_CAT_SCR 7.37 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_SCR 7.61 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_SCR 8.21 In certain embodiments, the immunogenetic biomarker comprises at least one HED score greater than a threshold value selected from the following table: HLA region HLA gene variable Threshold value Average HLA class I HLA-A HED_HLA_A_CAT_VR 3.88 Average HLA class I HLA-B HED_HLA_B_CAT_VR 9.37 Average HLA class I HLA-C HED_HLA_C_CAT_VR 0.00 Average HLA class I MEAN_MHCI HED_MEANI_CAT_VR 8.69 Average HLA class II HLA-DPB1 HED_HLA_P_CAT_VR 2.21 Average HLA class II HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_VR 12.68 Average HLA class II MEAN_MHCII HED_MEANII_CAT_VR 7.55 Average HLA class I HLA-A HED_HLA_A_CAT_CR 3.88 Average HLA class II MEAN_MHCII HED_MEANII_CAT_CR 7.67 Average HLA class I HLA-C HED_HLA_C_CAT_SCR 7.37 Average HLA class I MEAN_MHCI HED_MEANI_CAT_SCR 7.61 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 Average HLA class II MEAN_MHCII HED_MEANII_CAT_SCR 8.21

本文所描述的HED分數的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的HED分數的不存在預測在病毒抑制治療中止之後復發的高機率。The presence of the HED scores described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the HED scores described herein predicts a high chance of relapse after cessation of viral suppressive therapy.

在其他實施例中，HED分數係選自由HED HLA-A大於3.88之值、HED HLA-B大於9.37之值、HED HLA-C大於0.00之值、平均HED HLA I類大於8.69之值、HED HLA-DPB1大於2.21之值、HED HLA-DQB1大於11.98之值、HED HLA-DRB1大於12.68之值及平均HED HLA II類大於7.55之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。In other embodiments, the HED score is selected from the group consisting of HED HLA-A greater than 3.88, HED HLA-B greater than 9.37, HED HLA-C greater than 0.00, average HED HLA class I value greater than 8.69, HED HLA - A group consisting of a value of DPB1 greater than 2.21, a value of HED HLA-DQB1 greater than 11.98, a value of HED HLA-DRB1 greater than 12.68 and a value of average HED HLA class II greater than 7.55. The HED scores described herein can be used to predict the probability of virological relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，HED分數係選自由HED HLA-A大於3.88之值及平均HED HLA II類大於7.67之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。In other embodiments, the HED score is selected from the group consisting of a HED HLA-A value greater than 3.88 and a mean HED HLA class II value greater than 7.67. The HED scores described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，HED分數係選自由HED HLA-C大於7.37之值、平均HED HLA I類大於7.61之值、HED HLA-DRB1大於14.16之值及平均HED HLA II類大於8.21之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後持續臨床反應的機率。In other embodiments, the HED score is selected from the group consisting of HED HLA-C greater than 7.37, mean HED HLA class I greater than 7.61, HED HLA-DRB1 greater than 14.16, and mean HED HLA class II greater than 8.21 group. The HED scores described herein can be used to predict the probability of sustained clinical response after discontinuation of viral suppressive therapy for CHB.

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之LCR SNP：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。本文所描述的LCR SNP的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的LCR SNP的不存在預測在病毒抑制治療中止之後復發的高機率。In certain embodiments, the immunogenetic biomarker comprises an LCR SNP selected from the group consisting of: rs10426302, rs59537494, rs28366008, rs36625, rs635608, rs7595, rs731170, rs28513, rs12459334, rs11666535, rs4806807, rs39084367, rs39084367 rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、 rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、 rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。 The presence of the LCR SNPs described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the LCR SNPs described herein predicts a high probability of relapse following discontinuation of viral suppressive therapy.

在其他實施例中，LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627或其互補序列。本文所描述的LCR SNP可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。在其他實施例中，LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、 rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、 rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627或其互補序列。 The LCR SNPs described herein can be used to predict the probability of virological relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，LCR SNP係選自由以下組成之群：rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。本文所描述的LCR SNP可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。在其他實施例中，LCR SNP係選自由以下組成之群：rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、 rs10412569, AX-3232794851, rs622941 and rs60690598 or their complements. The LCR SNPs described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施方案中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之HLA-C對偶基因的存在：rs2394952中之對偶基因A、rs3130542中之對偶基因G、rs2894202中之對偶基因G、rs9264523中之對偶基因A、rs1049281中之對偶基因C、rs9264643中之對偶基因A、rs1130838中之對偶基因A、rs2394888中之對偶基因G、AX-83089411中之對偶基因T、rs2308622中之對偶基因C、rs9264416中之對偶基因A、rs2001181中之對偶基因T、rs3132499中之對偶基因T、rs3130532中之對偶基因G、rs3130941中之對偶基因G、rs3130528中之對偶基因C、rs3134782中之對偶基因A、rs3134769中之對偶基因C、rs3130521中之對偶基因C、rs3130695中之對偶基因G、rs3130685中之對偶基因T、rs2524119中之對偶基因C、rs3130527中之對偶基因C、rs2894186中之對偶基因C、rs3130439中之對偶基因A、rs3095254中之對偶基因G、rs9264189中之對偶基因C、rs2394943中之對偶基因C、rs9394047中之對偶基因C、rs3130948中之對偶基因T、rs9368666中之對偶基因G、rs3130942中之對偶基因T、rs3130688中之對偶基因T、rs3130536中之對偶基因G、rs3134750中之對偶基因G、rs4084090中之對偶基因G、rs9264127中之對偶基因G、rs9264039中之對偶基因A及rs3868078中之對偶基因T或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療中止之後的復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more HLA-C counterpart genes selected from the group consisting of: counterpart A in rs2394952, counterpart G in rs3130542, rs2894202 Dual gene G in rs9264523, dual gene C in rs1049281, dual gene A in rs9264643, dual gene A in rs1130838, dual gene G in rs2394888, dual gene T in AX-83089411, Dual gene C in rs2308622, dual gene A in rs9264416, dual gene T in rs2001181, dual gene T in rs3132499, dual gene G in rs3130532, dual gene G in rs3130941, dual gene C in rs3130528, dual gene in rs3134782 Dual gene A in rs3134769, dual gene C in rs3130521, dual gene G in rs3130695, dual gene T in rs3130685, dual gene C in rs2524119, dual gene C in rs3130527, dual gene in rs2894186 Gene C in rs3130439, Gene G in rs3095254, Gene C in rs9264189, Gene C in rs2394943, Gene C in rs9394047, Gene T in rs3130948, Gene T in rs9368666 Dual gene G, dual gene in rs3130942, dual gene T in rs3130688, dual gene G in rs3130536, dual gene G in rs3134750, dual gene G in rs4084090, dual gene G in rs9264127, dual gene in rs9264039 Gene A and the counterpart gene T in rs3868078 or its complement. The HLA-C dual genes described herein are protective against relapse after cessation of viral suppressive therapy for CHB.

在某些實施方案中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之HLA-C對偶基因的存在：rs2394952中之對偶基因A、rs3130542中之對偶基因G、rs2894202中之對偶基因G、rs9264523中之對偶基因A、rs1049281中之對偶基因C、rs9264643中之對偶基因A、rs1130838中之對偶基因A、rs2394888中之對偶基因G、AX-83089411中之對偶基因T、rs2308622中之對偶基因C、rs9264416中之對偶基因A、rs2001181中之對偶基因T、rs3132499中之對偶基因T、rs3130532中之對偶基因G、rs3130941中之對偶基因G、rs3130528中之對偶基因C、rs3134782中之對偶基因A、rs3134769中之對偶基因C、rs3130521中之對偶基因C、rs3130695中之對偶基因G、rs3130685中之對偶基因T、rs2524119中之對偶基因C、rs3130527中之對偶基因C、rs2894186中之對偶基因C、rs3130439中之對偶基因A、rs3095254中之對偶基因G、rs9264189中之對偶基因C、rs2394943中之對偶基因C、rs9394047中之對偶基因C、rs3130948中之對偶基因T、rs9368666中之對偶基因G、rs3130942中之對偶基因T、rs3130688中之對偶基因T、rs3130536中之對偶基因G及rs3134750中之對偶基因G或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療中止之後的病毒學復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more HLA-C counterpart genes selected from the group consisting of: counterpart A in rs2394952, counterpart G in rs3130542, rs2894202 Dual gene G in rs9264523, dual gene C in rs1049281, dual gene A in rs9264643, dual gene A in rs1130838, dual gene G in rs2394888, dual gene T in AX-83089411, Dual gene C in rs2308622, dual gene A in rs9264416, dual gene T in rs2001181, dual gene T in rs3132499, dual gene G in rs3130532, dual gene G in rs3130941, dual gene C in rs3130528, dual gene in rs3134782 Dual gene A in rs3134769, dual gene C in rs3130521, dual gene G in rs3130695, dual gene T in rs3130685, dual gene C in rs2524119, dual gene C in rs3130527, dual gene in rs2894186 Gene C in rs3130439, Gene G in rs3095254, Gene C in rs9264189, Gene C in rs2394943, Gene C in rs9394047, Gene T in rs3130948, Gene T in rs9368666 The counterpart G, the counterpart T in rs3130942, the counterpart T in rs3130688, the counterpart G in rs3130536, and the counterpart G in rs3134750 or their complementary sequences. The HLA-C dual genes described herein are protective against virological relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之HLA-C對偶基因的存在：rs4084090中之對偶基因G、rs9264127中之對偶基因G、rs9264039中之對偶基因A及rs3868078中之對偶基因T或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療中止之後的臨床復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more HLA-C counterpart genes selected from the group consisting of: counterpart G in rs4084090, counterpart G in rs9264127, rs9264039 The counterpart gene A in rs3868078 and the counterpart gene T in rs3868078 or its complement. The HLA-C dual genes described herein are protective against clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs10426302中之對偶基因A、rs59537494中之對偶基因C、rs28366008中之對偶基因C、rs36625中之對偶基因G、rs635608中之對偶基因T、rs7595中之對偶基因C、rs731170中之對偶基因A、rs28513中之對偶基因A、rs12459334中之對偶基因T、rs11666535中之對偶基因T、rs4806807中之對偶基因T、rs11084367中之對偶基因A、rs39714中之對偶基因G、rs1654474中之對偶基因C、rs12462907中之對偶基因C、rs775893中之對偶基因G、rs10416527中之對偶基因A、rs4441391中之對偶基因A、rs40167中之對偶基因A、rs11084339中之對偶基因A、rs775875中之對偶基因A、rs2304225中之對偶基因C、rs4077076中之對偶基因A、rs4442924中之對偶基因A、rs4806527中之對偶基因A、rs12608979中之對偶基因C、COSV52557220之rs3765013中之對偶基因A、rs12462181中之對偶基因T、COSV52550169之rs2075731中之對偶基因T、rs12608988中之對偶基因G、rs190480734中之對偶基因G、rs1654452中之對偶基因G、rs11879415中之對偶基因T、rs653560中之對偶基因G、rs11084387中之對偶基因G、rs11672111中之對偶基因G、rs10424969中之對偶基因T、rs77389424中之對偶基因T、CM1111041之rs3745902中之對偶基因C、rs11672983中之對偶基因G、rs17836364中之對偶基因A、rs34549987中之對偶基因C、rs11668526中之對偶基因T、rs11667105中之對偶基因G、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs73618328中之對偶基因C、rs270785中之對偶基因C、rs76522818中之對偶基因C、rs62131745中之對偶基因C、rs2241384中之對偶基因G、rs1325158中之對偶基因T、rs10500318中之對偶基因G、rs3816051中之對偶基因T、rs34508934中之對偶基因C、rs12460627中之對偶基因G、rs11667812中之對偶基因C、rs12974194中之對偶基因C、rs17836364中之對偶基因A、rs11669431中之對偶基因C、rs12984962中之對偶基因C、rs1761462中之對偶基因T、rs4806464中之對偶基因C、rs34190750中之對偶基因C、rs28681595中之對偶基因T、rs12610675中之對偶基因G、rs12463051中之對偶基因A、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs41275824中之對偶基因C、rs2241384中之對偶基因G、rs12983338中之對偶基因T、rs272408中之對偶基因T、rs10412569中之對偶基因G、AX-3232794851中之對偶基因T、rs622941中之對偶基因G及rs60690598中之對偶基因C或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療中止之後的復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more LCR counterpart genes selected from the group consisting of: counterpart A in rs10426302, counterpart C in rs59537494, and one of rs28366008 Dual gene C, dual gene G in rs36625, dual gene T in rs635608, dual gene C in rs7595, dual gene A in rs731170, dual gene A in rs28513, dual gene T in rs12459334, dual gene in rs11666535 Gene T, paired gene T in rs4806807, paired gene A in rs11084367, paired gene G in rs39714, paired gene C in rs1654474, paired gene C in rs12462907, paired gene G in rs775893, paired gene in rs10416527 A. Dual gene A in rs4441391, dual gene A in rs40167, dual gene A in rs11084339, dual gene A in rs775875, dual gene C in rs2304225, dual gene A in rs4077076, dual gene A in rs4442924 , Dual gene A in rs4806527, dual gene C in rs12608979, dual gene A in rs3765013 of COSV52557220, dual gene T in rs12462181, dual gene T in rs2075731 of COSV52550169, dual gene G in rs12608988, and dual gene G in rs190480734 Dual gene G, dual gene in rs1654452, dual gene T in rs11879415, dual gene G in rs653560, dual gene G in rs11084387, dual gene G in rs11672111, dual gene T in rs10424969, dual gene in rs77389424 Gene T, the counterpart gene C in rs3745902 of CM1111041, the counterpart gene G in rs11672983, the counterpart gene A in rs17836364, the counterpart gene C in rs34549987, the counterpart gene T in rs11668526, the counterpart gene G in rs11667105, the counterpart gene in rs1749282 Dual gene G, dual gene A in rs1654660, dual gene C in rs73618328, dual gene C in rs270785, dual gene C in rs76522818, dual gene C in rs62131745, dual gene G in rs2241384, dual gene in rs1325158 Gene T, the counterpart of rs10500318, G, rs38 Dual gene T in 16051, dual gene C in rs34508934, dual gene G in rs12460627, dual gene C in rs11667812, dual gene C in rs12974194, dual gene A in rs17836364, dual gene C in rs11669431, dual gene C in rs12984962 Dual gene C in rs1761462, dual gene C in rs4806464, dual gene C in rs34190750, dual gene T in rs28681595, dual gene G in rs12610675, dual gene A in rs12463051, dual gene in rs1749282 Dual gene G in rs1654660, dual gene C in rs41275824, dual gene G in rs2241384, dual gene T in rs12983338, dual gene T in rs272408, dual gene G in rs10412569, AX-3232794851 The counterpart gene T in rs622941, the counterpart gene G in rs622941, and the counterpart gene C in rs60690598 or their complements. The LCR dual genes described herein are protective against relapse after cessation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs10426302中之對偶基因A、rs59537494中之對偶基因C、rs28366008中之對偶基因C、rs36625中之對偶基因G、rs635608中之對偶基因T、rs7595中之對偶基因C、rs731170中之對偶基因A、rs28513中之對偶基因A、rs12459334中之對偶基因T、rs11666535中之對偶基因T、rs4806807中之對偶基因T、rs11084367中之對偶基因A、rs39714中之對偶基因G、rs1654474中之對偶基因C、rs12462907中之對偶基因C、rs775893中之對偶基因G、rs10416527中之對偶基因A、rs4441391中之對偶基因A、rs40167中之對偶基因A、rs11084339中之對偶基因A、rs775875中之對偶基因A、rs2304225中之對偶基因C、rs4077076中之對偶基因A、rs4442924中之對偶基因A、rs4806527中之對偶基因A、rs12608979中之對偶基因C、COSV52557220之rs3765013中之對偶基因A、rs12462181中之對偶基因T、COSV52550169之rs2075731中之對偶基因T、rs12608988中之對偶基因G、rs190480734中之對偶基因G、rs1654452中之對偶基因G、rs11879415中之對偶基因T、rs653560中之對偶基因G、rs11084387中之對偶基因G、rs11672111中之對偶基因G、rs10424969中之對偶基因T、rs77389424中之對偶基因T、CM1111041之rs3745902中之對偶基因C、rs11672983中之對偶基因G、rs17836364中之對偶基因A、rs34549987中之對偶基因C、rs11668526中之對偶基因T、rs11667105中之對偶基因G、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs73618328中之對偶基因C、rs270785中之對偶基因C、rs76522818中之對偶基因C、rs62131745中之對偶基因C、rs2241384中之對偶基因G、rs1325158中之對偶基因T、rs10500318中之對偶基因G、rs3816051中之對偶基因T、rs34508934中之對偶基因C及rs12460627中之對偶基因G或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療中止之後的病毒學復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more LCR counterpart genes selected from the group consisting of: counterpart A in rs10426302, counterpart C in rs59537494, and one of rs28366008 Dual gene C, dual gene G in rs36625, dual gene T in rs635608, dual gene C in rs7595, dual gene A in rs731170, dual gene A in rs28513, dual gene T in rs12459334, dual gene in rs11666535 Gene T, paired gene T in rs4806807, paired gene A in rs11084367, paired gene G in rs39714, paired gene C in rs1654474, paired gene C in rs12462907, paired gene G in rs775893, paired gene in rs10416527 A. Dual gene A in rs4441391, dual gene A in rs40167, dual gene A in rs11084339, dual gene A in rs775875, dual gene C in rs2304225, dual gene A in rs4077076, dual gene A in rs4442924 , Dual gene A in rs4806527, dual gene C in rs12608979, dual gene A in rs3765013 of COSV52557220, dual gene T in rs12462181, dual gene T in rs2075731 of COSV52550169, dual gene G in rs12608988, and dual gene G in rs190480734 Dual gene G, dual gene in rs1654452, dual gene T in rs11879415, dual gene G in rs653560, dual gene G in rs11084387, dual gene G in rs11672111, dual gene T in rs10424969, dual gene in rs77389424 Gene T, the counterpart gene C in rs3745902 of CM1111041, the counterpart gene G in rs11672983, the counterpart gene A in rs17836364, the counterpart gene C in rs34549987, the counterpart gene T in rs11668526, the counterpart gene G in rs11667105, the counterpart gene in rs1749282 Dual gene G, dual gene A in rs1654660, dual gene C in rs73618328, dual gene C in rs270785, dual gene C in rs76522818, dual gene C in rs62131745, dual gene G in rs2241384, dual gene in rs1325158 Gene T, the counterpart of rs10500318, G, rs38 The counterpart T in 16051, the counterpart C in rs34508934, and the counterpart G in rs12460627 or their complements. The LCR dual genes described herein are protective against virological relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs11667812中之對偶基因C、rs12974194中之對偶基因C、rs17836364中之對偶基因A、rs11669431中之對偶基因C、rs12984962中之對偶基因C、rs1761462中之對偶基因T、rs4806464中之對偶基因C、rs34190750中之對偶基因C、rs28681595中之對偶基因T、rs12610675中之對偶基因G、rs12463051中之對偶基因A、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs41275824中之對偶基因C、rs2241384中之對偶基因G、rs12983338中之對偶基因T、rs272408中之對偶基因T、rs10412569中之對偶基因G、AX-3232794851中之對偶基因T、rs622941中之對偶基因G及rs60690598中之對偶基因C或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療中止之後的臨床復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more LCR counterpart genes selected from the group consisting of: counterpart C in rs11667812, counterpart C in rs12974194, one of rs17836364 Dual gene A, dual gene C in rs11669431, dual gene C in rs12984962, dual gene T in rs1761462, dual gene C in rs4806464, dual gene C in rs34190750, dual gene T in rs28681595, dual gene in rs12610675 Gene G, paired gene A in rs12463051, paired gene G in rs1749282, paired gene A in rs1654660, paired gene C in rs41275824, paired gene G in rs2241384, paired gene T in rs12983338, paired gene in rs272408 T, the counterpart G in rs10412569, the counterpart T in AX-3232794851, the counterpart G in rs622941, and the counterpart C in rs60690598 or their complements. The LCR dual genes described herein are protective against clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，CHB感染之病毒抑制治療係NUC治療。該NUC可為替諾福韋、恩替卡韋、拉米夫定、阿德福韋或替比夫定。In certain embodiments, the viral suppressive therapy for CHB infection is NUC therapy. The NUC can be tenofovir, entecavir, lamivudine, adefovir, or telbivudine.

在某些實施例中，該方法進一步包括偵測與該復發相關聯之一或多個另外生物標記。此類生物標記之實例包括但不限於治療結束時的HbsAg量、治療前的HBeAg量、HBV DNA量、ALT、AST及HBV RNA。In certain embodiments, the method further comprises detecting one or more additional biomarkers associated with the recurrence. Examples of such biomarkers include, but are not limited to, the amount of HbsAg at the end of treatment, the amount of HBeAg before treatment, the amount of HBV DNA, ALT, AST, and HBV RNA.

本文亦提供使用本文所描述的免疫遺傳生物標記治療有需要個體中慢性B型肝炎(CHB)感染之方法。Also provided herein are methods of treating chronic hepatitis B (CHB) infection in an individual in need thereof using the immunogenetic biomarkers described herein.

在一個一般態樣中，本申請案提供一種治療有需要個體中慢性B型肝炎(CHB)感染之方法，該方法包括： a. 對該個體投與病毒抑制治療以治療CHB感染； b. 偵測從該個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i. 人類白血球抗原(HLA)對偶基因； ii. 一或多個HLA-C單核苷酸多型性(SNP)； iii. HLA演化多樣性(HED)分數；及 iv. 白血球受體複合物(LCR) SNP； c. 若在生物樣本中偵測到步驟b之該一或多個免疫遺傳生物標記，則一旦達成病毒抑制，立刻中止該病毒抑制治療，較佳地，該病毒抑制治療係在治療2年之後中止；或 若在生物樣本中未偵測到步驟b之免疫遺傳生物標記，則繼續該病毒抑制治療，甚至在達成病毒抑制之後，及/或對該個體投與一種另外或不同病毒抑制治療。 In one general aspect, the present application provides a method of treating chronic hepatitis B (CHB) infection in an individual in need thereof, the method comprising: a. administering to the individual viral suppressive therapy to treat CHB infection; b. Detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. Human leukocyte antigen (HLA) pair genes; ii. One or more HLA-C single nucleotide polytypes (SNPs); iii. HLA Evolutionary Diversity (HED) score; and iv. Leukocyte receptor complex (LCR) SNPs; c. If the one or more immunogenetic biomarkers of step b are detected in the biological sample, once viral suppression is achieved, the viral suppressive treatment is immediately discontinued, preferably, the viral suppressive treatment is performed after 2 years of treatment suspend; or If the immunogenetic biomarker of step b is not detected in the biological sample, the viral suppression therapy is continued, even after viral suppression is achieved, and/or an additional or different viral suppression therapy is administered to the individual.

如本文所用，當免疫遺傳生物標記係HED分數時，「偵測從個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在」係指判定生物樣本中之HED分數。As used herein, when the immunogenetic biomarker is the HED score, "detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from an individual" refers to determining the HED score in the biological sample .

在某些實施例中，免疫遺傳生物標記的偵測係在投與病毒抑制治療之後進行。In certain embodiments, detection of immunogenetic biomarkers is performed after administration of viral suppressive therapy.

在某些實施例中，提供使用根據本發明之一個實施例之免疫遺傳生物標記預測經診斷患有CHB的個體中病毒抑制治療中止之後復發之方法。該方法包括：(a) 從經診斷患有CHB的個體獲得生物樣本；b) 判定該生物樣本是否包含本文所描述的一或多個免疫遺傳生物標記。In certain embodiments, methods are provided for predicting relapse following discontinuation of viral suppressive therapy in an individual diagnosed with CHB using an immunogenetic biomarker according to one embodiment of the present invention. The method includes: (a) obtaining a biological sample from an individual diagnosed with CHB; b) determining whether the biological sample contains one or more immunogenetic biomarkers described herein.

在某些實施例中，免疫遺傳生物標記包含HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在。HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在預測病毒抑制治療中止之後復發的低機率，較佳係病毒學復發的低機率。HLA對偶基因B*51或C*15的不存在或HLA對偶基因C*07的存在預測病毒抑制治療中止之後復發的高機率，較佳係病毒學復發的高機率。在其他實施例中，HLA對偶基因C*15係C*15:02及HLA對偶基因C*07係C*07:02。In certain embodiments, the immunogenetic biomarker comprises the presence of HLA counterpart B*51 or C*15 or the absence of HLA counterpart C*07. The presence of the HLA counterpart B*51 or C*15 or the absence of the HLA counterpart C*07 predicts a low chance of relapse after cessation of viral suppressive therapy, preferably a low chance of virological relapse. The absence of the HLA counterpart B*51 or C*15 or the presence of the HLA counterpart C*07 predicts a high probability of relapse, preferably virological relapse, after cessation of viral suppressive therapy. In other embodiments, the HLA counterpart C*15 is C*15:02 and the HLA counterpart C*07 is C*07:02.

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之HLA-C SNP：rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、rs9264039及rs3868078，或其互補序列。本文所描述的HLA-C SNP的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的HLA-C SNP的不存在預測在病毒抑制治療中止之後復發的高機率。In certain embodiments, the immunogenetic biomarker comprises an HLA-C SNP selected from the group consisting of: rs2394952, rs3130542, rs2894202, rs9264523, rs1049281, rs9264643, rs1130838, rs2394888, AX-83089411, rs2308622, rs91640416, rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、 rs9264039 and rs3868078, or their complements. The presence of the HLA-C SNPs described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the HLA-C SNPs described herein predicts a high probability of relapse following discontinuation of viral suppressive therapy.

在其他實施例中，HLA-C SNP係選自由以下組成之群： rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750，或其互補序列。本文所描述的HLC-C SNPs可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。在其他實施例中，HLA-C SNP係選自由以下組成之群： rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、 rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750，或其互補序列。 The HLC-C SNPs described herein can be used to predict the probability of virological relapse following discontinuation of virological suppression therapy for CHB.

在其他實施例中，HLA-C SNP係選自由s4084090、rs9264127、rs9264039及rs3868078或其互補序列組成之群。本文所描述的HLC-C SNP可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。In other embodiments, the HLA-C SNPs are selected from the group consisting of s4084090, rs9264127, rs9264039 and rs3868078 or their complements. The HLC-C SNPs described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該免疫遺傳生物標記包含至少一個大於選自下表之臨限值之HED分數： HLA 區域 HLA 基因 變數 臨限值 平均HLA I類 HLA-A HED_HLA_A_CAT_VR 3.88 平均HLA I類 HLA-B HED_HLA_B_CAT_VR 9.37 平均HLA I類 HLA-C HED_HLA_C_CAT_VR 0.00 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_VR 8.69 平均HLA II類 HLA-DPB1 HED_HLA_P_CAT_VR 2.21 平均HLA II類 HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_VR 12.68 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_VR 7.55 平均HLA I類 HLA-A HED_HLA_A_CAT_CR 3.88 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_CR 7.67 平均HLA I類 HLA-C HED_HLA_C_CAT_SCR 7.37 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_SCR 7.61 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_SCR 8.21 In certain embodiments, the immunogenetic biomarker comprises at least one HED score greater than a threshold value selected from the following table: HLA region HLA gene variable Threshold value Average HLA class I HLA-A HED_HLA_A_CAT_VR 3.88 Average HLA class I HLA-B HED_HLA_B_CAT_VR 9.37 Average HLA class I HLA-C HED_HLA_C_CAT_VR 0.00 Average HLA class I MEAN_MHCI HED_MEANI_CAT_VR 8.69 Average HLA class II HLA-DPB1 HED_HLA_P_CAT_VR 2.21 Average HLA class II HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_VR 12.68 Average HLA class II MEAN_MHCII HED_MEANII_CAT_VR 7.55 Average HLA class I HLA-A HED_HLA_A_CAT_CR 3.88 Average HLA class II MEAN_MHCII HED_MEANII_CAT_CR 7.67 Average HLA class I HLA-C HED_HLA_C_CAT_SCR 7.37 Average HLA class I MEAN_MHCI HED_MEANI_CAT_SCR 7.61 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 Average HLA class II MEAN_MHCII HED_MEANII_CAT_SCR 8.21

本文所描述的HED分數的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的HED分數的不存在預測在病毒抑制治療中止之後復發的高機率。The presence of the HED scores described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the HED scores described herein predicts a high chance of relapse after cessation of viral suppressive therapy.

在其他實施例中，HED分數係選自由HED HLA-A大於3.88之值、HED HLA-B大於9.37之值、HED HLA-C大於0.00之值、平均HED HLA I類大於8.69之值、HED HLA-DPB1大於2.21之值、HED HLA-DQB1大於11.98之值、HED HLA-DRB1大於12.68之值及平均HED HLA II類大於7.55之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。In other embodiments, the HED score is selected from the group consisting of HED HLA-A greater than 3.88, HED HLA-B greater than 9.37, HED HLA-C greater than 0.00, average HED HLA class I value greater than 8.69, HED HLA - A group consisting of a value of DPB1 greater than 2.21, a value of HED HLA-DQB1 greater than 11.98, a value of HED HLA-DRB1 greater than 12.68 and a value of average HED HLA class II greater than 7.55. The HED scores described herein can be used to predict the probability of virological relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，HED分數係選自由HED HLA-A大於3.88之值及平均HED HLA II類大於7.67之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。In other embodiments, the HED score is selected from the group consisting of a HED HLA-A value greater than 3.88 and a mean HED HLA class II value greater than 7.67. The HED scores described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，HED分數係選自由HED HLA-C大於7.37之值、平均HED HLA I類大於7.61之值、HED HLA-DRB1大於14.16之值及平均HED HLA II類大於8.21之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後持續臨床反應的機率。In other embodiments, the HED score is selected from the group consisting of HED HLA-C greater than 7.37, mean HED HLA class I greater than 7.61, HED HLA-DRB1 greater than 14.16, and mean HED HLA class II greater than 8.21 group. The HED scores described herein can be used to predict the probability of sustained clinical response after discontinuation of viral suppressive therapy for CHB.

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之LCR SNP：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。本文所描述的LCR SNP的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的LCR SNP的不存在預測在病毒抑制治療中止之後復發的高機率。In certain embodiments, the immunogenetic biomarker comprises an LCR SNP selected from the group consisting of: rs10426302, rs59537494, rs28366008, rs36625, rs635608, rs7595, rs731170, rs28513, rs12459334, rs11666535, rs4806807, rs39084367, rs39084367 rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、 rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、 rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。 The presence of the LCR SNPs described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the LCR SNPs described herein predicts a high probability of relapse following discontinuation of viral suppressive therapy.

在其他實施例中，LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627或其互補序列。本文所描述的LCR SNP可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。在其他實施例中，LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、 rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、 rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627或其互補序列。 The LCR SNPs described herein can be used to predict the probability of virological relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，LCR SNP係選自由以下組成之群：rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。本文所描述的LCR SNP可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。在其他實施例中，LCR SNP係選自由以下組成之群：rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、 rs10412569, AX-3232794851, rs622941 and rs60690598 or their complements. The LCR SNPs described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施方案中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之HLA-C對偶基因的存在：rs2394952中之對偶基因A、rs3130542中之對偶基因G、rs2894202中之對偶基因G、rs9264523中之對偶基因A、rs1049281中之對偶基因C、rs9264643中之對偶基因A、rs1130838中之對偶基因A、rs2394888中之對偶基因G、AX-83089411中之對偶基因T、rs2308622中之對偶基因C、rs9264416中之對偶基因A、rs2001181中之對偶基因T、rs3132499中之對偶基因T、rs3130532中之對偶基因G、rs3130941中之對偶基因G、rs3130528中之對偶基因C、rs3134782中之對偶基因A、rs3134769中之對偶基因C、rs3130521中之對偶基因C、rs3130695中之對偶基因G、rs3130685中之對偶基因T、rs2524119中之對偶基因C、rs3130527中之對偶基因C、rs2894186中之對偶基因C、rs3130439中之對偶基因A、rs3095254中之對偶基因G、rs9264189中之對偶基因C、rs2394943中之對偶基因C、rs9394047中之對偶基因C、rs3130948中之對偶基因T、rs9368666中之對偶基因G、rs3130942中之對偶基因T、rs3130688中之對偶基因T、rs3130536中之對偶基因G、rs3134750中之對偶基因G、rs4084090中之對偶基因G、rs9264127中之對偶基因G、rs9264039中之對偶基因A及rs3868078中之對偶基因T或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more HLA-C counterpart genes selected from the group consisting of: counterpart A in rs2394952, counterpart G in rs3130542, rs2894202 Dual gene G in rs9264523, dual gene C in rs1049281, dual gene A in rs9264643, dual gene A in rs1130838, dual gene G in rs2394888, dual gene T in AX-83089411, Dual gene C in rs2308622, dual gene A in rs9264416, dual gene T in rs2001181, dual gene T in rs3132499, dual gene G in rs3130532, dual gene G in rs3130941, dual gene C in rs3130528, dual gene in rs3134782 Dual gene A in rs3134769, dual gene C in rs3130521, dual gene G in rs3130695, dual gene T in rs3130685, dual gene C in rs2524119, dual gene C in rs3130527, dual gene in rs2894186 Gene C in rs3130439, Gene G in rs3095254, Gene C in rs9264189, Gene C in rs2394943, Gene C in rs9394047, Gene T in rs3130948, Gene T in rs9368666 Dual gene G, dual gene in rs3130942, dual gene T in rs3130688, dual gene G in rs3130536, dual gene G in rs3134750, dual gene G in rs4084090, dual gene G in rs9264127, dual gene in rs9264039 Gene A and the counterpart gene T in rs3868078 or its complement. The HLA-C dual genes described herein are protective against relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施方案中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之HLA-C對偶基因的存在：rs2394952中之對偶基因A、rs3130542中之對偶基因G、rs2894202中之對偶基因G、rs9264523中之對偶基因A、rs1049281中之對偶基因C、rs9264643中之對偶基因A、rs1130838中之對偶基因A、rs2394888中之對偶基因G、AX-83089411中之對偶基因T、rs2308622中之對偶基因C、rs9264416中之對偶基因A、rs2001181中之對偶基因T、rs3132499中之對偶基因T、rs3130532中之對偶基因G、rs3130941中之對偶基因G、rs3130528中之對偶基因C、rs3134782中之對偶基因A、rs3134769中之對偶基因C、rs3130521中之對偶基因C、rs3130695中之對偶基因G、rs3130685中之對偶基因T、rs2524119中之對偶基因C、rs3130527中之對偶基因C、rs2894186中之對偶基因C、rs3130439中之對偶基因A、rs3095254中之對偶基因G、rs9264189中之對偶基因C、rs2394943中之對偶基因C、rs9394047中之對偶基因C、rs3130948中之對偶基因T、rs9368666中之對偶基因G、rs3130942中之對偶基因T、rs3130688中之對偶基因T、rs3130536中之對偶基因G及rs3134750中之對偶基因G或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的病毒學復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more HLA-C counterpart genes selected from the group consisting of: counterpart A in rs2394952, counterpart G in rs3130542, rs2894202 Dual gene G in rs9264523, dual gene C in rs1049281, dual gene A in rs9264643, dual gene A in rs1130838, dual gene G in rs2394888, dual gene T in AX-83089411, Dual gene C in rs2308622, dual gene A in rs9264416, dual gene T in rs2001181, dual gene T in rs3132499, dual gene G in rs3130532, dual gene G in rs3130941, dual gene C in rs3130528, dual gene in rs3134782 Dual gene A in rs3134769, dual gene C in rs3130521, dual gene G in rs3130695, dual gene T in rs3130685, dual gene C in rs2524119, dual gene C in rs3130527, dual gene in rs2894186 Gene C in rs3130439, Gene G in rs3095254, Gene C in rs9264189, Gene C in rs2394943, Gene C in rs9394047, Gene T in rs3130948, Gene T in rs9368666 The counterpart G, the counterpart T in rs3130942, the counterpart T in rs3130688, the counterpart G in rs3130536, and the counterpart G in rs3134750 or their complementary sequences. The HLA-C dual genes described herein are protective against virological relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由組成之群之HLA-C對偶基因的存在：rs4084090中之對偶基因G、rs9264127中之對偶基因G、rs9264039中之對偶基因A及rs3868078中之對偶基因T或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的臨床復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more HLA-C counterpart genes selected from the group consisting of: counterpart G in rs4084090, counterpart G in rs9264127, in rs9264039 The counterpart gene A and the counterpart gene T in rs3868078 or its complement. The HLA-C dual genes described herein are protective against clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs10426302中之對偶基因A、rs59537494中之對偶基因C、rs28366008中之對偶基因C、rs36625中之對偶基因G、rs635608中之對偶基因T、rs7595中之對偶基因C、rs731170中之對偶基因A、rs28513中之對偶基因A、rs12459334中之對偶基因T、rs11666535中之對偶基因T、rs4806807中之對偶基因T、rs11084367中之對偶基因A、rs39714中之對偶基因G、rs1654474中之對偶基因C、rs12462907中之對偶基因C、rs775893中之對偶基因G、rs10416527中之對偶基因A、rs4441391中之對偶基因A、rs40167中之對偶基因A、rs11084339中之對偶基因A、rs775875中之對偶基因A、rs2304225中之對偶基因C、rs4077076中之對偶基因A、rs4442924中之對偶基因A、rs4806527中之對偶基因A、rs12608979中之對偶基因C、COSV52557220之rs3765013中之對偶基因A、rs12462181中之對偶基因T、COSV52550169之rs2075731中之對偶基因T、rs12608988中之對偶基因G、rs190480734中之對偶基因G、rs1654452中之對偶基因G、rs11879415中之對偶基因T、rs653560中之對偶基因G、rs11084387中之對偶基因G、rs11672111中之對偶基因G、rs10424969中之對偶基因T、rs77389424中之對偶基因T、CM1111041之rs3745902中之對偶基因C、rs11672983中之對偶基因G、rs17836364中之對偶基因A、rs34549987中之對偶基因C、rs11668526中之對偶基因T、rs11667105中之對偶基因G、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs73618328中之對偶基因C、rs270785中之對偶基因C、rs76522818中之對偶基因C、rs62131745中之對偶基因C、rs2241384中之對偶基因G、rs1325158中之對偶基因T、rs10500318中之對偶基因G、rs3816051中之對偶基因T、rs34508934中之對偶基因C、rs12460627中之對偶基因G、rs11667812中之對偶基因C、rs12974194中之對偶基因C、rs17836364中之對偶基因A、rs11669431中之對偶基因C、rs12984962中之對偶基因C、rs1761462中之對偶基因T、rs4806464中之對偶基因C、rs34190750中之對偶基因C、rs28681595中之對偶基因T、rs12610675中之對偶基因G、rs12463051中之對偶基因A、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs41275824中之對偶基因C、rs2241384中之對偶基因G、rs12983338中之對偶基因T、rs272408中之對偶基因T、rs10412569中之對偶基因G、AX-3232794851中之對偶基因T、rs622941中之對偶基因G及rs60690598中之對偶基因C或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more LCR counterpart genes selected from the group consisting of: counterpart A in rs10426302, counterpart C in rs59537494, and one of rs28366008 Dual gene C, dual gene G in rs36625, dual gene T in rs635608, dual gene C in rs7595, dual gene A in rs731170, dual gene A in rs28513, dual gene T in rs12459334, dual gene in rs11666535 Gene T, paired gene T in rs4806807, paired gene A in rs11084367, paired gene G in rs39714, paired gene C in rs1654474, paired gene C in rs12462907, paired gene G in rs775893, paired gene in rs10416527 A. Dual gene A in rs4441391, dual gene A in rs40167, dual gene A in rs11084339, dual gene A in rs775875, dual gene C in rs2304225, dual gene A in rs4077076, dual gene A in rs4442924 , Dual gene A in rs4806527, dual gene C in rs12608979, dual gene A in rs3765013 of COSV52557220, dual gene T in rs12462181, dual gene T in rs2075731 of COSV52550169, dual gene G in rs12608988, and dual gene G in rs190480734 Dual gene G, dual gene in rs1654452, dual gene T in rs11879415, dual gene G in rs653560, dual gene G in rs11084387, dual gene G in rs11672111, dual gene T in rs10424969, dual gene in rs77389424 Gene T, the counterpart gene C in rs3745902 of CM1111041, the counterpart gene G in rs11672983, the counterpart gene A in rs17836364, the counterpart gene C in rs34549987, the counterpart gene T in rs11668526, the counterpart gene G in rs11667105, the counterpart gene in rs1749282 Dual gene G, dual gene A in rs1654660, dual gene C in rs73618328, dual gene C in rs270785, dual gene C in rs76522818, dual gene C in rs62131745, dual gene G in rs2241384, dual gene in rs1325158 Gene T, the counterpart of rs10500318, G, rs38 Dual gene T in 16051, dual gene C in rs34508934, dual gene G in rs12460627, dual gene C in rs11667812, dual gene C in rs12974194, dual gene A in rs17836364, dual gene C in rs11669431, dual gene C in rs12984962 Dual gene C in rs1761462, dual gene C in rs4806464, dual gene C in rs34190750, dual gene T in rs28681595, dual gene G in rs12610675, dual gene A in rs12463051, dual gene in rs1749282 Dual gene G in rs1654660, dual gene C in rs41275824, dual gene G in rs2241384, dual gene T in rs12983338, dual gene T in rs272408, dual gene G in rs10412569, AX-3232794851 The counterpart gene T in rs622941, the counterpart gene G in rs622941, and the counterpart gene C in rs60690598 or their complements. The LCR dual genes described herein are protective against relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs10426302中之對偶基因A、rs59537494中之對偶基因C、rs28366008中之對偶基因C、rs36625中之對偶基因G、rs635608中之對偶基因T、rs7595中之對偶基因C、rs731170中之對偶基因A、rs28513中之對偶基因A、rs12459334中之對偶基因T、rs11666535中之對偶基因T、rs4806807中之對偶基因T、rs11084367中之對偶基因A、rs39714中之對偶基因G、rs1654474中之對偶基因C、rs12462907中之對偶基因C、rs775893中之對偶基因G、rs10416527中之對偶基因A、rs4441391中之對偶基因A、rs40167中之對偶基因A、rs11084339中之對偶基因A、rs775875中之對偶基因A、rs2304225中之對偶基因C、rs4077076中之對偶基因A、rs4442924中之對偶基因A、rs4806527中之對偶基因A、rs12608979中之對偶基因C、COSV52557220之rs3765013中之對偶基因A、rs12462181中之對偶基因T、COSV52550169之rs2075731中之對偶基因T、rs12608988中之對偶基因G、rs190480734中之對偶基因G、rs1654452中之對偶基因G、rs11879415中之對偶基因T、rs653560中之對偶基因G、rs11084387中之對偶基因G、rs11672111中之對偶基因G、rs10424969中之對偶基因T、rs77389424中之對偶基因T、CM1111041之rs3745902中之對偶基因C、rs11672983中之對偶基因G、rs17836364中之對偶基因A、rs34549987中之對偶基因C、rs11668526中之對偶基因T、rs11667105中之對偶基因G、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs73618328中之對偶基因C、rs270785中之對偶基因C、rs76522818中之對偶基因C、rs62131745中之對偶基因C、rs2241384中之對偶基因G、rs1325158中之對偶基因T、rs10500318中之對偶基因G、rs3816051中之對偶基因T、rs34508934中之對偶基因C及rs12460627中之對偶基因G或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的病毒學復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more LCR counterpart genes selected from the group consisting of: counterpart A in rs10426302, counterpart C in rs59537494, and one of rs28366008 Dual gene C, dual gene G in rs36625, dual gene T in rs635608, dual gene C in rs7595, dual gene A in rs731170, dual gene A in rs28513, dual gene T in rs12459334, dual gene in rs11666535 Gene T, paired gene T in rs4806807, paired gene A in rs11084367, paired gene G in rs39714, paired gene C in rs1654474, paired gene C in rs12462907, paired gene G in rs775893, paired gene in rs10416527 A. Dual gene A in rs4441391, dual gene A in rs40167, dual gene A in rs11084339, dual gene A in rs775875, dual gene C in rs2304225, dual gene A in rs4077076, dual gene A in rs4442924 , Dual gene A in rs4806527, dual gene C in rs12608979, dual gene A in rs3765013 of COSV52557220, dual gene T in rs12462181, dual gene T in rs2075731 of COSV52550169, dual gene G in rs12608988, and dual gene G in rs190480734 Dual gene G, dual gene in rs1654452, dual gene T in rs11879415, dual gene G in rs653560, dual gene G in rs11084387, dual gene G in rs11672111, dual gene T in rs10424969, dual gene in rs77389424 Gene T, the counterpart gene C in rs3745902 of CM1111041, the counterpart gene G in rs11672983, the counterpart gene A in rs17836364, the counterpart gene C in rs34549987, the counterpart gene T in rs11668526, the counterpart gene G in rs11667105, the counterpart gene in rs1749282 Dual gene G, dual gene A in rs1654660, dual gene C in rs73618328, dual gene C in rs270785, dual gene C in rs76522818, dual gene C in rs62131745, dual gene G in rs2241384, dual gene in rs1325158 Gene T, the counterpart of rs10500318, G, rs38 The counterpart T in 16051, the counterpart C in rs34508934, and the counterpart G in rs12460627 or their complements. The LCR dual genes described herein are protective against virological relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs11667812中之對偶基因C、rs12974194中之對偶基因C、rs17836364中之對偶基因A、rs11669431中之對偶基因C、rs12984962中之對偶基因C、rs1761462中之對偶基因T、rs4806464中之對偶基因C、rs34190750中之對偶基因C、rs28681595中之對偶基因T、rs12610675中之對偶基因G、rs12463051中之對偶基因A、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs41275824中之對偶基因C、rs2241384中之對偶基因G、rs12983338中之對偶基因T、rs272408中之對偶基因T、rs10412569中之對偶基因G、AX-3232794851中之對偶基因T、rs622941中之對偶基因G及rs60690598中之對偶基因C或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的臨床復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more LCR counterpart genes selected from the group consisting of: counterpart C in rs11667812, counterpart C in rs12974194, one of rs17836364 Dual gene A, dual gene C in rs11669431, dual gene C in rs12984962, dual gene T in rs1761462, dual gene C in rs4806464, dual gene C in rs34190750, dual gene T in rs28681595, dual gene in rs12610675 Gene G, paired gene A in rs12463051, paired gene G in rs1749282, paired gene A in rs1654660, paired gene C in rs41275824, paired gene G in rs2241384, paired gene T in rs12983338, paired gene in rs272408 T, the counterpart G in rs10412569, the counterpart T in AX-3232794851, the counterpart G in rs622941, and the counterpart C in rs60690598 or their complements. The LCR dual genes described herein are protective against clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，CHB感染之病毒抑制治療係NUC治療。該NUC可為替諾福韋、恩替卡韋、拉米夫定、阿德福韋或替比夫定。In certain embodiments, the viral suppressive therapy for CHB infection is NUC therapy. The NUC can be tenofovir, entecavir, lamivudine, adefovir, or telbivudine.

在某些實施例中，該方法進一步包括偵測與該復發相關聯之一或多個另外生物標記。此類生物標記之實例包括但不限於治療結束時的HbsAg量、治療前的HBeAg量、HBV DNA量、ALT、AST及HBV RNA。In certain embodiments, the method further comprises detecting one or more additional biomarkers associated with the recurrence. Examples of such biomarkers include, but are not limited to, the amount of HbsAg at the end of treatment, the amount of HBeAg before treatment, the amount of HBV DNA, ALT, AST, and HBV RNA.

在某些實施例中，使用熟習此項技術者已知的任何方法來判定生物樣本中一或多個免疫遺傳生物標記的存在或不存在。In certain embodiments, the presence or absence of one or more immunogenetic biomarkers in a biological sample is determined using any method known to those skilled in the art.

在某些實施例中，若在生物樣本中偵測到一或多個免疫遺傳生物標記，則一旦達成病毒抑制，立刻中止治療，較佳地在治療2年之後。In certain embodiments, treatment is discontinued as soon as viral suppression is achieved, preferably after 2 years of treatment, if one or more immunogenetic biomarkers are detected in the biological sample.

在某些實施例中，若在生物樣本中未偵測到免疫遺傳生物標記，則一旦達成病毒抑制立刻繼續病毒抑制治療，較佳地在治療2年之後，及/或對個體投與進一步或不同病毒抑制治療。In certain embodiments, if no immunogenetic biomarkers are detected in the biological sample, viral suppression therapy is continued once viral suppression is achieved, preferably after 2 years of therapy, and/or further or Different viral suppressive treatments.

在某些實施例中，該個體在病毒抑制治療之後的一年、兩年、三年或四年或其間的任何時間時或之後達成HBV DNA ＜ 60 IU/mL、ALT ＜ 80 U/L或HBeAg陰性。在其他實施例中，該個體然後中止病毒抑制治療。In certain embodiments, the individual achieves HBV DNA < 60 IU/mL, ALT < 80 U/L, or at or after one year, two years, three years, or four years, or any time in between, following viral suppression therapy HBeAg negative. In other embodiments, the individual then discontinues viral suppression therapy.

在其他實施例中，個體在病毒抑制治療中止之後3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後沒有病毒學復發或臨床復發，且其中該病毒學復發經識別為HBV DNA ≥ 2000 IU/ml或HBeAg陽性，及該臨床復發經識別為i) HBV DNA ≥ 2000 IU/ml或HBeAg陽性，且ii) ALT ≥ 80 U/L。In other embodiments, the subject has no virological relapse or clinical relapse at or after 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, or any time in between, after cessation of viral suppressive therapy Relapse where the virological relapse is identified as HBV DNA ≥ 2000 IU/ml or HBeAg positive, and the clinical relapse is identified as i) HBV DNA ≥ 2000 IU/ml or HBeAg positive, and ii) ALT ≥ 80 U/ L.

本文亦提供治療有需要個體中慢性B型肝炎(CHB)感染之方法，該方法包括： a. 對該個體投與病毒抑制治療以治療CHB感染； b. 偵測從該個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i. 人類白血球抗原(HLA)對偶基因； ii. 一或多個HLA-C單核苷酸多型性(SNP)； iii. HLA演化多樣性(HED)分數；及 iv. 白血球受體複合物(LCR) SNP； c. 當個體中CHB感染得以抑制時，中止病毒抑制治療，及 d. 若在生物樣本中未偵測到免疫遺傳生物標記，則在中止之後少於兩年對該個體投與病毒抑制治療或另一病毒抑制治療。 Also provided herein are methods of treating chronic hepatitis B (CHB) infection in an individual in need thereof, the methods comprising: a. administering to the individual viral suppressive therapy to treat CHB infection; b. Detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. Human leukocyte antigen (HLA) pair genes; ii. One or more HLA-C single nucleotide polytypes (SNPs); iii. HLA Evolutionary Diversity (HED) score; and iv. Leukocyte receptor complex (LCR) SNPs; c. Discontinue viral suppression therapy when CHB infection is suppressed in the individual, and d. If no immunogenetic biomarker is detected in the biological sample, administer viral suppressive therapy or another viral suppressive therapy to the individual less than two years after discontinuation.

如本文所用，當免疫遺傳生物標記係HED分數時，「偵測從個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在」係指判定生物樣本中之HED分數。As used herein, when the immunogenetic biomarker is the HED score, "detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from an individual" refers to determining the HED score in the biological sample .

在某些實施例中，免疫遺傳生物標記包含HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在。HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在預測病毒抑制治療中止之後復發的低機率，較佳係病毒學復發的低機率。HLA對偶基因B*51或C*15的不存在或HLA對偶基因C*07的存在預測病毒抑制治療中止之後復發的高機率，較佳係病毒學復發的高機率。在其他實施例中，HLA對偶基因C*15係C*15:02及HLA對偶基因C*07係C*07:02。In certain embodiments, the immunogenetic biomarker comprises the presence of HLA counterpart B*51 or C*15 or the absence of HLA counterpart C*07. The presence of the HLA counterpart B*51 or C*15 or the absence of the HLA counterpart C*07 predicts a low chance of relapse after cessation of viral suppressive therapy, preferably a low chance of virological relapse. The absence of the HLA counterpart B*51 or C*15 or the presence of the HLA counterpart C*07 predicts a high probability of relapse, preferably virological relapse, after cessation of viral suppressive therapy. In other embodiments, the HLA counterpart C*15 is C*15:02 and the HLA counterpart C*07 is C*07:02.

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之HLA-C SNP：rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、rs9264039及rs3868078或其互補序列。本文所描述的HLA-C SNP的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的HLA-C SNP的不存在預測在病毒抑制治療中止之後復發的高機率。In certain embodiments, the immunogenetic biomarker comprises an HLA-C SNP selected from the group consisting of: rs2394952, rs3130542, rs2894202, rs9264523, rs1049281, rs9264643, rs1130838, rs2394888, AX-83089411, rs2308622, rs91640416, rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、 rs9264039 and rs3868078 or their complements. The presence of the HLA-C SNPs described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the HLA-C SNPs described herein predicts a high probability of relapse following discontinuation of viral suppressive therapy.

在其他實施例中，HLA-C SNP係選自由以下組成之群： rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750或其互補序列。本文所描述的HLC-C SNP可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。在其他實施例中，HLA-C SNP係選自由以下組成之群： rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、 rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750或其互補序列。 The HLC-C SNPs described herein can be used to predict the probability of virological relapse following discontinuation of virological suppression therapy for CHB.

在其他實施例中，HLA-C SNP係選自由s4084090、rs9264127、rs9264039及rs3868078或其互補序列組成之群。本文所描述的HLC-C SNP可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。In other embodiments, the HLA-C SNPs are selected from the group consisting of s4084090, rs9264127, rs9264039 and rs3868078 or their complements. The HLC-C SNPs described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該免疫遺傳生物標記包含至少一個大於選自下表之臨限值之HED分數： HLA 區域 HLA 基因 變數 臨限值 平均HLA I類 HLA-A HED_HLA_A_CAT_VR 3.88 平均HLA I類 HLA-B HED_HLA_B_CAT_VR 9.37 平均HLA I類 HLA-C HED_HLA_C_CAT_VR 0.00 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_VR 8.69 平均HLA II類 HLA-DPB1 HED_HLA_P_CAT_VR 2.21 平均HLA II類 HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_VR 12.68 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_VR 7.55 平均HLA I類 HLA-A HED_HLA_A_CAT_CR 3.88 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_CR 7.67 平均HLA I類 HLA-C HED_HLA_C_CAT_SCR 7.37 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_SCR 7.61 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_SCR 8.21 In certain embodiments, the immunogenetic biomarker comprises at least one HED score greater than a threshold value selected from the following table: HLA region HLA gene variable Threshold value Average HLA class I HLA-A HED_HLA_A_CAT_VR 3.88 Average HLA class I HLA-B HED_HLA_B_CAT_VR 9.37 Average HLA class I HLA-C HED_HLA_C_CAT_VR 0.00 Average HLA class I MEAN_MHCI HED_MEANI_CAT_VR 8.69 Average HLA class II HLA-DPB1 HED_HLA_P_CAT_VR 2.21 Average HLA class II HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_VR 12.68 Average HLA class II MEAN_MHCII HED_MEANII_CAT_VR 7.55 Average HLA class I HLA-A HED_HLA_A_CAT_CR 3.88 Average HLA class II MEAN_MHCII HED_MEANII_CAT_CR 7.67 Average HLA class I HLA-C HED_HLA_C_CAT_SCR 7.37 Average HLA class I MEAN_MHCI HED_MEANI_CAT_SCR 7.61 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 Average HLA class II MEAN_MHCII HED_MEANII_CAT_SCR 8.21

本文所描述的HED分數的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的HED分數的不存在預測在病毒抑制治療中止之後復發的高機率。The presence of the HED scores described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the HED scores described herein predicts a high chance of relapse after cessation of viral suppressive therapy.

在其他實施例中，HED分數係選自由HED HLA-A大於3.88之值、HED HLA-B大於9.37之值、HED HLA-C大於0.00之值、平均HED HLA I類大於8.69之值、HED HLA-DPB1大於2.21之值、HED HLA-DQB1大於11.98之值、HED HLA-DRB1大於12.68之值及平均HED HLA II類大於7.55之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。In other embodiments, the HED score is selected from the group consisting of HED HLA-A greater than 3.88, HED HLA-B greater than 9.37, HED HLA-C greater than 0.00, average HED HLA class I value greater than 8.69, HED HLA - A group consisting of a value of DPB1 greater than 2.21, a value of HED HLA-DQB1 greater than 11.98, a value of HED HLA-DRB1 greater than 12.68 and a value of average HED HLA class II greater than 7.55. The HED scores described herein can be used to predict the probability of virological relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，HED分數係選自由HED HLA-A大於3.88之值及平均HED HLA II類大於7.67之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。In other embodiments, the HED score is selected from the group consisting of a HED HLA-A value greater than 3.88 and a mean HED HLA class II value greater than 7.67. The HED scores described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，HED分數係選自由HED HLA-C大於7.37之值、平均HED HLA I類大於7.61之值、HED HLA-DRB1大於14.16之值及平均HED HLA II類大於8.21之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後持續臨床反應的機率。In other embodiments, the HED score is selected from the group consisting of HED HLA-C greater than 7.37, mean HED HLA class I greater than 7.61, HED HLA-DRB1 greater than 14.16, and mean HED HLA class II greater than 8.21 group. The HED scores described herein can be used to predict the probability of sustained clinical response after discontinuation of viral suppressive therapy for CHB.

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之LCR SNP：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。本文所描述的LCR SNP的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的LCR SNP的不存在預測在病毒抑制治療中止之後復發的高機率。In certain embodiments, the immunogenetic biomarker comprises an LCR SNP selected from the group consisting of: rs10426302, rs59537494, rs28366008, rs36625, rs635608, rs7595, rs731170, rs28513, rs12459334, rs11666535, rs4806807, rs39084367, rs39084367 rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、 rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、 rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。 The presence of the LCR SNPs described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the LCR SNPs described herein predicts a high probability of relapse following discontinuation of viral suppressive therapy.

在其他實施例中，LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627或其互補序列。本文所描述的LCR SNP可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。在其他實施例中，LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、 rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、 rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627或其互補序列。 The LCR SNPs described herein can be used to predict the probability of virological relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，LCR SNP係選自由以下組成之群：rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。本文所描述的LCR SNP可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。在其他實施例中，LCR SNP係選自由以下組成之群：rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、 rs10412569, AX-3232794851, rs622941 and rs60690598 or their complements. The LCR SNPs described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施方案中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之HLA-C對偶基因的存在：rs2394952中之對偶基因A、rs3130542中之對偶基因G、rs2894202中之對偶基因G、rs9264523中之對偶基因A、rs1049281中之對偶基因C、rs9264643中之對偶基因A、rs1130838中之對偶基因A、rs2394888中之對偶基因G、AX-83089411中之對偶基因T、rs2308622中之對偶基因C、rs9264416中之對偶基因A、rs2001181中之對偶基因T、rs3132499中之對偶基因T、rs3130532中之對偶基因G、rs3130941中之對偶基因G、rs3130528中之對偶基因C、rs3134782中之對偶基因A、rs3134769中之對偶基因C、rs3130521中之對偶基因C、rs3130695中之對偶基因G、rs3130685中之對偶基因T、rs2524119中之對偶基因C、rs3130527中之對偶基因C、rs2894186中之對偶基因C、rs3130439中之對偶基因A、rs3095254中之對偶基因G、rs9264189中之對偶基因C、rs2394943中之對偶基因C、rs9394047中之對偶基因C、rs3130948中之對偶基因T、rs9368666中之對偶基因G、rs3130942中之對偶基因T、rs3130688中之對偶基因T、rs3130536中之對偶基因G、rs3134750中之對偶基因G、rs4084090中之對偶基因G、rs9264127中之對偶基因G、rs9264039中之對偶基因A及rs3868078中之對偶基因T或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more HLA-C counterpart genes selected from the group consisting of: counterpart A in rs2394952, counterpart G in rs3130542, rs2894202 Dual gene G in rs9264523, dual gene C in rs1049281, dual gene A in rs9264643, dual gene A in rs1130838, dual gene G in rs2394888, dual gene T in AX-83089411, Dual gene C in rs2308622, dual gene A in rs9264416, dual gene T in rs2001181, dual gene T in rs3132499, dual gene G in rs3130532, dual gene G in rs3130941, dual gene C in rs3130528, dual gene in rs3134782 Dual gene A in rs3134769, dual gene C in rs3130521, dual gene G in rs3130695, dual gene T in rs3130685, dual gene C in rs2524119, dual gene C in rs3130527, dual gene in rs2894186 Gene C in rs3130439, Gene G in rs3095254, Gene C in rs9264189, Gene C in rs2394943, Gene C in rs9394047, Gene T in rs3130948, Gene T in rs9368666 Dual gene G, dual gene in rs3130942, dual gene T in rs3130688, dual gene G in rs3130536, dual gene G in rs3134750, dual gene G in rs4084090, dual gene G in rs9264127, dual gene in rs9264039 Gene A and the counterpart gene T in rs3868078 or its complement. The HLA-C dual genes described herein are protective against relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施方案中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之HLA-C對偶基因的存在：rs2394952中之對偶基因A、rs3130542中之對偶基因G、rs2894202中之對偶基因G、rs9264523中之對偶基因A、rs1049281中之對偶基因C、rs9264643中之對偶基因A、rs1130838中之對偶基因A、rs2394888中之對偶基因G、AX-83089411中之對偶基因T、rs2308622中之對偶基因C、rs9264416中之對偶基因A、rs2001181中之對偶基因T、rs3132499中之對偶基因T、rs3130532中之對偶基因G、rs3130941中之對偶基因G、rs3130528中之對偶基因C、rs3134782中之對偶基因A、rs3134769中之對偶基因C、rs3130521中之對偶基因C、rs3130695中之對偶基因G、rs3130685中之對偶基因T、rs2524119中之對偶基因C、rs3130527中之對偶基因C、rs2894186中之對偶基因C、rs3130439中之對偶基因A、rs3095254中之對偶基因G、rs9264189中之對偶基因C、rs2394943中之對偶基因C、rs9394047中之對偶基因C、rs3130948中之對偶基因T、rs9368666中之對偶基因G、rs3130942中之對偶基因T、rs3130688中之對偶基因T、rs3130536中之對偶基因G及rs3134750中之對偶基因G或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的病毒學復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more HLA-C counterpart genes selected from the group consisting of: counterpart A in rs2394952, counterpart G in rs3130542, rs2894202 Dual gene G in rs9264523, dual gene C in rs1049281, dual gene A in rs9264643, dual gene A in rs1130838, dual gene G in rs2394888, dual gene T in AX-83089411, Dual gene C in rs2308622, dual gene A in rs9264416, dual gene T in rs2001181, dual gene T in rs3132499, dual gene G in rs3130532, dual gene G in rs3130941, dual gene C in rs3130528, dual gene in rs3134782 Dual gene A in rs3134769, dual gene C in rs3130521, dual gene G in rs3130695, dual gene T in rs3130685, dual gene C in rs2524119, dual gene C in rs3130527, dual gene in rs2894186 Gene C in rs3130439, Gene G in rs3095254, Gene C in rs9264189, Gene C in rs2394943, Gene C in rs9394047, Gene T in rs3130948, Gene T in rs9368666 The counterpart G, the counterpart T in rs3130942, the counterpart T in rs3130688, the counterpart G in rs3130536, and the counterpart G in rs3134750 or their complementary sequences. The HLA-C dual genes described herein are protective against virological relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之HLA-C對偶基因的存在：rs4084090中之對偶基因G、rs9264127中之對偶基因G、rs9264039中之對偶基因A及rs3868078中之對偶基因T或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的臨床復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more HLA-C counterpart genes selected from the group consisting of: counterpart G in rs4084090, counterpart G in rs9264127, rs9264039 The counterpart gene A in rs3868078 and the counterpart gene T in rs3868078 or its complement. The HLA-C dual genes described herein are protective against clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs10426302中之對偶基因A、rs59537494中之對偶基因C、rs28366008中之對偶基因C、rs36625中之對偶基因G、rs635608中之對偶基因T、rs7595中之對偶基因C、rs731170中之對偶基因A、rs28513中之對偶基因A、rs12459334中之對偶基因T、rs11666535中之對偶基因T、rs4806807中之對偶基因T、rs11084367中之對偶基因A、rs39714中之對偶基因G、rs1654474中之對偶基因C、rs12462907中之對偶基因C、rs775893中之對偶基因G、rs10416527中之對偶基因A、rs4441391中之對偶基因A、rs40167中之對偶基因A、rs11084339中之對偶基因A、rs775875中之對偶基因A、rs2304225中之對偶基因C、rs4077076中之對偶基因A、rs4442924中之對偶基因A、rs4806527中之對偶基因A、rs12608979中之對偶基因C、COSV52557220之rs3765013中之對偶基因A、rs12462181中之對偶基因T、COSV52550169之rs2075731中之對偶基因T、rs12608988中之對偶基因G、rs190480734中之對偶基因G、rs1654452中之對偶基因G、rs11879415中之對偶基因T、rs653560中之對偶基因G、rs11084387中之對偶基因G、rs11672111中之對偶基因G、rs10424969中之對偶基因T、rs77389424中之對偶基因T、CM1111041之rs3745902中之對偶基因C、rs11672983中之對偶基因G、rs17836364中之對偶基因A、rs34549987中之對偶基因C、rs11668526中之對偶基因T、rs11667105中之對偶基因G、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs73618328中之對偶基因C、rs270785中之對偶基因C、rs76522818中之對偶基因C、rs62131745中之對偶基因C、rs2241384中之對偶基因G、rs1325158中之對偶基因T、rs10500318中之對偶基因G、rs3816051中之對偶基因T、rs34508934中之對偶基因C、rs12460627中之對偶基因G、rs11667812中之對偶基因C、rs12974194中之對偶基因C、rs17836364中之對偶基因A、rs11669431中之對偶基因C、rs12984962中之對偶基因C、rs1761462中之對偶基因T、rs4806464中之對偶基因C、rs34190750中之對偶基因C、rs28681595中之對偶基因T、rs12610675中之對偶基因G、rs12463051中之對偶基因A、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs41275824中之對偶基因C、rs2241384中之對偶基因G、rs12983338中之對偶基因T、rs272408中之對偶基因T、rs10412569中之對偶基因G、AX-3232794851中之對偶基因T、rs622941中之對偶基因G及rs60690598中之對偶基因C或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more LCR counterpart genes selected from the group consisting of: counterpart A in rs10426302, counterpart C in rs59537494, and one of rs28366008 Dual gene C, dual gene G in rs36625, dual gene T in rs635608, dual gene C in rs7595, dual gene A in rs731170, dual gene A in rs28513, dual gene T in rs12459334, dual gene in rs11666535 Gene T, paired gene T in rs4806807, paired gene A in rs11084367, paired gene G in rs39714, paired gene C in rs1654474, paired gene C in rs12462907, paired gene G in rs775893, paired gene in rs10416527 A. Dual gene A in rs4441391, dual gene A in rs40167, dual gene A in rs11084339, dual gene A in rs775875, dual gene C in rs2304225, dual gene A in rs4077076, dual gene A in rs4442924 , Dual gene A in rs4806527, dual gene C in rs12608979, dual gene A in rs3765013 of COSV52557220, dual gene T in rs12462181, dual gene T in rs2075731 of COSV52550169, dual gene G in rs12608988, and dual gene G in rs190480734 Dual gene G, dual gene in rs1654452, dual gene T in rs11879415, dual gene G in rs653560, dual gene G in rs11084387, dual gene G in rs11672111, dual gene T in rs10424969, dual gene in rs77389424 Gene T, the counterpart gene C in rs3745902 of CM1111041, the counterpart gene G in rs11672983, the counterpart gene A in rs17836364, the counterpart gene C in rs34549987, the counterpart gene T in rs11668526, the counterpart gene G in rs11667105, the counterpart gene in rs1749282 Dual gene G, dual gene A in rs1654660, dual gene C in rs73618328, dual gene C in rs270785, dual gene C in rs76522818, dual gene C in rs62131745, dual gene G in rs2241384, dual gene in rs1325158 Gene T, the counterpart of rs10500318, G, rs38 Gene T in 16051, Gene C in rs34508934, Gene G in rs12460627, Gene C in rs11667812, Gene C in rs12974194, Gene A in rs17836364, Gene C in rs11669431, Gene C in rs12984962 Dual gene C in rs1761462, dual gene C in rs4806464, dual gene C in rs34190750, dual gene T in rs28681595, dual gene G in rs12610675, dual gene A in rs12463051, dual gene in rs1749282 Dual gene G in rs1654660, dual gene C in rs41275824, dual gene G in rs2241384, dual gene T in rs12983338, dual gene T in rs272408, dual gene G in rs10412569, AX-3232794851 The counterpart gene T in rs622941, the counterpart gene G in rs622941, and the counterpart gene C in rs60690598 or their complements. The LCR dual genes described herein are protective against relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs10426302中之對偶基因A、rs59537494中之對偶基因C、rs28366008中之對偶基因C、rs36625中之對偶基因G、rs635608中之對偶基因T、rs7595中之對偶基因C、rs731170中之對偶基因A、rs28513中之對偶基因A、rs12459334中之對偶基因T、rs11666535中之對偶基因T、rs4806807中之對偶基因T、rs11084367中之對偶基因A、rs39714中之對偶基因G、rs1654474中之對偶基因C、rs12462907中之對偶基因C、rs775893中之對偶基因G、rs10416527中之對偶基因A、rs4441391中之對偶基因A、rs40167中之對偶基因A、rs11084339中之對偶基因A、rs775875中之對偶基因A、rs2304225中之對偶基因C、rs4077076中之對偶基因A、rs4442924中之對偶基因A、rs4806527中之對偶基因A、rs12608979中之對偶基因C、COSV52557220之rs3765013中之對偶基因A、rs12462181中之對偶基因T、COSV52550169之rs2075731中之對偶基因T、rs12608988中之對偶基因G、rs190480734中之對偶基因G、rs1654452中之對偶基因G、rs11879415中之對偶基因T、rs653560中之對偶基因G、rs11084387中之對偶基因G、rs11672111中之對偶基因G、rs10424969中之對偶基因T、rs77389424中之對偶基因T、CM1111041之rs3745902中之對偶基因C、rs11672983中之對偶基因G、rs17836364中之對偶基因A、rs34549987中之對偶基因C、rs11668526中之對偶基因T、rs11667105中之對偶基因G、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs73618328中之對偶基因C、rs270785中之對偶基因C、rs76522818中之對偶基因C、rs62131745中之對偶基因C、rs2241384中之對偶基因G、rs1325158中之對偶基因T、rs10500318中之對偶基因G、rs3816051中之對偶基因T、rs34508934中之對偶基因C及rs12460627中之對偶基因G或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的病毒學復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more LCR counterpart genes selected from the group consisting of: counterpart A in rs10426302, counterpart C in rs59537494, and one of rs28366008 Dual gene C, dual gene G in rs36625, dual gene T in rs635608, dual gene C in rs7595, dual gene A in rs731170, dual gene A in rs28513, dual gene T in rs12459334, dual gene in rs11666535 Gene T, paired gene T in rs4806807, paired gene A in rs11084367, paired gene G in rs39714, paired gene C in rs1654474, paired gene C in rs12462907, paired gene G in rs775893, paired gene in rs10416527 A. Dual gene A in rs4441391, dual gene A in rs40167, dual gene A in rs11084339, dual gene A in rs775875, dual gene C in rs2304225, dual gene A in rs4077076, dual gene A in rs4442924 , Dual gene A in rs4806527, dual gene C in rs12608979, dual gene A in rs3765013 of COSV52557220, dual gene T in rs12462181, dual gene T in rs2075731 of COSV52550169, dual gene G in rs12608988, and dual gene G in rs190480734 Dual gene G, dual gene in rs1654452, dual gene T in rs11879415, dual gene G in rs653560, dual gene G in rs11084387, dual gene G in rs11672111, dual gene T in rs10424969, dual gene in rs77389424 Gene T, the counterpart gene C in rs3745902 of CM1111041, the counterpart gene G in rs11672983, the counterpart gene A in rs17836364, the counterpart gene C in rs34549987, the counterpart gene T in rs11668526, the counterpart gene G in rs11667105, the counterpart gene in rs1749282 Dual gene G, dual gene A in rs1654660, dual gene C in rs73618328, dual gene C in rs270785, dual gene C in rs76522818, dual gene C in rs62131745, dual gene G in rs2241384, dual gene in rs1325158 Gene T, the counterpart of rs10500318, G, rs38 The counterpart T in 16051, the counterpart C in rs34508934, and the counterpart G in rs12460627 or their complements. The LCR dual genes described herein are protective against virological relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該方法進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs11667812中之對偶基因C、rs12974194中之對偶基因C、rs17836364中之對偶基因A、rs11669431中之對偶基因C、rs12984962中之對偶基因C、rs1761462中之對偶基因T、rs4806464中之對偶基因C、rs34190750中之對偶基因C、rs28681595中之對偶基因T、rs12610675中之對偶基因G、rs12463051中之對偶基因A、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs41275824中之對偶基因C、rs2241384中之對偶基因G、rs12983338中之對偶基因T、rs272408中之對偶基因T、rs10412569中之對偶基因G、AX-3232794851中之對偶基因T、rs622941中之對偶基因G及rs60690598中之對偶基因C或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的臨床復發。In certain embodiments, the method further comprises detecting the presence in the biological sample of one or more LCR counterpart genes selected from the group consisting of: counterpart C in rs11667812, counterpart C in rs12974194, one of rs17836364 Dual gene A, dual gene C in rs11669431, dual gene C in rs12984962, dual gene T in rs1761462, dual gene C in rs4806464, dual gene C in rs34190750, dual gene T in rs28681595, dual gene in rs12610675 Gene G, paired gene A in rs12463051, paired gene G in rs1749282, paired gene A in rs1654660, paired gene C in rs41275824, paired gene G in rs2241384, paired gene T in rs12983338, paired gene in rs272408 T, the counterpart G in rs10412569, the counterpart T in AX-3232794851, the counterpart G in rs622941, and the counterpart C in rs60690598 or their complements. The LCR dual genes described herein are protective against clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，CHB感染之病毒抑制治療係NUC治療。該NUC可為替諾福韋、恩替卡韋、拉米夫定、阿德福韋或替比夫定。In certain embodiments, the viral suppressive therapy for CHB infection is NUC therapy. The NUC can be tenofovir, entecavir, lamivudine, adefovir, or telbivudine.

在某些實施例中，CHB感染之病毒抑制治療係NUC治療。該NUC可為替諾福韋、恩替卡韋、拉米夫定、阿德福韋或替比夫定。In certain embodiments, the viral suppressive therapy for CHB infection is NUC therapy. The NUC can be tenofovir, entecavir, lamivudine, adefovir, or telbivudine.

在某些實施例中，使用熟習此項技術者已知的任何方法來判定生物樣本中一或多個免疫遺傳生物標記的存在或不存在。In certain embodiments, the presence or absence of one or more immunogenetic biomarkers in a biological sample is determined using any method known to those skilled in the art.

在某些實施例中，該個體在病毒抑制治療之後的一年、兩年、三年或四年或其間的任何時間時或之後達成HBV DNA ＜ 60 IU/mL、ALT ＜ 80 U/L或HBeAg陰性。在其他實施例中，該個體然後中止病毒抑制治療。In certain embodiments, the individual achieves HBV DNA < 60 IU/mL, ALT < 80 U/L, or at or after one year, two years, three years, or four years, or any time in between, following viral suppression therapy HBeAg negative. In other embodiments, the individual then discontinues viral suppression therapy.

在其他實施例中，個體在病毒抑制治療中止之後3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後沒有病毒學復發或臨床復發，且其中該病毒學復發經識別為HBV DNA ≥ 2000 IU/ml或HBeAg陽性，及該臨床復發經識別為i) HBV DNA ≥ 2000 IU/ml或HBeAg陽性，且ii) ALT ≥ 80 U/L。In other embodiments, the subject has no virological relapse or clinical relapse at or after 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, or any time in between, after cessation of viral suppressive therapy Relapse where the virological relapse is identified as HBV DNA ≥ 2000 IU/ml or HBeAg positive, and the clinical relapse is identified as i) HBV DNA ≥ 2000 IU/ml or HBeAg positive, and ii) ALT ≥ 80 U/ L.

在某些實施例中，樣本係組織樣本、細胞樣本或血液樣本。較佳地，樣本係血液樣本。In certain embodiments, the sample is a tissue sample, a cell sample, or a blood sample. Preferably, the sample is a blood sample.

在某些實施例中，樣本係在病毒抑制治療之前、期間或之後獲得。In certain embodiments, the sample is obtained before, during, or after viral suppressive therapy.

在某些實施例中，CHB感染在病毒抑制治療中止之時得以抑制。在一個實施例中，當個體在病毒抑制治療之後的一年、兩年、三年或四年或其間的任何時間時或之後達成HBV DNA ＜ 60 IU/mL、ALT ＜ 80 U/L或HBeAg陰性時，個體中止病毒抑制治療。較佳地，個體在病毒抑制治療中止時達成HBsAg ＜ 100 IU/mL。In certain embodiments, CHB infection is suppressed upon discontinuation of viral suppressive therapy. In one embodiment, when the individual achieves HBV DNA < 60 IU/mL, ALT < 80 U/L or HBeAg at or after one, two, three or four years or any time in between following viral suppression therapy When negative, the subject discontinued viral suppression therapy. Preferably, the individual achieves HBsAg < 100 IU/mL at the time of discontinuation of viral suppressive therapy.

在某些實施例中，該方法進一步包括在病毒抑制治療中止之後的3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後測定HBV DNA、ALT及HBsAg。In certain embodiments, the method further comprises determining at or after 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, or any time in between, after cessation of viral suppressive therapy HBV DNA, ALT and HBsAg.

在某些實施例中，個體在中止病毒抑制治療之後的3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後沒有病毒學復發，且病毒學復發經識別為HBV DNA ≥ 2000 IU/ml或HBeAg陽性。In certain embodiments, the subject has no virological relapse at or after 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, or any time in between, after discontinuation of viral suppressive therapy , and virological recurrence was identified as HBV DNA ≥ 2000 IU/ml or HBeAg positive.

在某個實施例中，個體在病毒抑制治療中止之後3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後沒有臨床復發，及該臨床復發經識別為i) HBV DNA ≥ 2000 IU/ml或HBeAg陽性，且ii) ALT ≥ 80 U/L。In a certain embodiment, the subject is free of clinical relapse at or after 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, or any time in between, after cessation of viral suppressive therapy, and This clinical relapse was identified as i) HBV DNA ≥ 2000 IU/ml or positive HBeAg, and ii) ALT ≥ 80 U/L.

有鑑於本揭示，可使用此項技術中已知或本文所描述之任何方法偵測SNP的存在。根據本申請案之實施例，SNP或對偶基因係藉由選自由以下組成之群之方法來判定：DNA定序、限制片段長度多型性(RFLP分析)、對偶基因特異性寡核苷酸(ASO)分析、變性/溫度梯度凝膠電泳(DGGE/TGGE)、單股構象多型性(SSCP)分析、雙去氧指紋分析(ddF)、焦磷酸定序分析、acycloprime分析、反向墨點轉漬、基因晶片(GeneChip)微陣列、動態對偶基因特異性雜交(DASH)、肽核酸(PNA)及鎖核酸(LNA)探針、TaqMan、分子信標、嵌入染料、FRET引子、AlphaScreen、SNPstream、遺傳位元分析(GBA)、多重微定序、SNaPshot、MassEXTEND、MassArray、GOOD檢定、微陣列微定序、陣列式引子延伸(APEX)、微陣列引子延伸、標籤陣列、經編碼之微球、模板導向併入(TDI)、螢光偏振、比色寡核苷酸連接檢定(OLA)、序列編碼OLA、微陣列連接、連接酶鏈反應、扣鎖(Padlock)探針、滾環擴增及侵入物(Invader)檢定。In view of the present disclosure, the presence of SNPs can be detected using any method known in the art or described herein. According to embodiments of the present application, SNPs or counterparts are determined by a method selected from the group consisting of DNA sequencing, restriction fragment length polymorphism (RFLP analysis), counterpart-specific oligonucleotides ( ASO) analysis, denaturing/temperature gradient gel electrophoresis (DGGE/TGGE), single-strand conformational polymorphism (SSCP) analysis, dideoxy fingerprint analysis (ddF), pyrosequencing analysis, acycloprime analysis, reverse ink dot analysis Transfection, GeneChip Microarray, Dynamic Dual Gene-Specific Hybridization (DASH), Peptide Nucleic Acid (PNA) and Locked Nucleic Acid (LNA) Probes, TaqMan, Molecular Beacons, Intercalating Dyes, FRET Primers, AlphaScreen, SNPstream , Genetic Bit Analysis (GBA), Multiplex Microsequencing, SNaPshot, MassEXTEND, MassArray, GOOD Assay, Microarray Microsequencing, Arrayed Primer Extension (APEX), Microarray Primer Extension, Tag Array, Encoded Microspheres , Template-Directed Incorporation (TDI), Fluorescence Polarization, Colorimetric Oligonucleotide Ligation Assay (OLA), Sequence-Encoded OLA, Microarray Ligation, Ligase Chain Reaction, Padlock Probes, Rolling Circle Amplification and Invader checks.

本文亦提供用於治療有需要個體中慢性B型肝炎病毒(CHB)感染之病毒抑制治療。Also provided herein are viral suppressive therapies for the treatment of chronic hepatitis B virus (CHB) infection in individuals in need thereof.

在一個一般態樣中，本申請案提供一種病毒抑制治療，特別是包含核苷酸或核苷類似物(NUC)之病毒抑制治療，更特別是包含選自由替諾福韋、恩替卡韋、拉米夫定、阿德福韋及替比夫定組成之群之NUC之病毒抑制治療，其用於治療有需要個體中慢性B型肝炎病毒(CHB)感染，其中該治療包括： a. 對該個體投與病毒抑制治療以治療CHB感染； b. 偵測從該個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i. 人類白血球抗原(HLA)對偶基因； ii. 一或多個HLA-C單核苷酸多型性(SNP)； iii. HLA演化多樣性(HED)分數；及 iv. 白血球受體複合物(LCR) SNP； c. 若在生物樣本中偵測到步驟b之該一或多個免疫遺傳生物標記，則一旦達成病毒抑制，立刻中止該病毒抑制治療，較佳地，該病毒抑制治療係在治療2年之後中止；或 若在生物樣本中未偵測到步驟b之免疫遺傳生物標記，則繼續該病毒抑制治療，甚至在達成病毒抑制之後，及/或對該個體投與一種另外或不同病毒抑制治療。 In a general aspect, the present application provides a viral suppressive therapy, particularly a viral suppressive therapy comprising a nucleotide or nucleoside analog (NUC), more particularly a viral suppressant therapy comprising a group selected from tenofovir, entecavir, lamic acid Viral suppression therapy for NUC of the group consisting of vudine, adefovir and telbivudine for the treatment of chronic hepatitis B virus (CHB) infection in individuals in need thereof, wherein the treatment comprises: a. administering to the individual viral suppressive therapy to treat CHB infection; b. Detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. Human leukocyte antigen (HLA) pair genes; ii. One or more HLA-C single nucleotide polytypes (SNPs); iii. HLA Evolutionary Diversity (HED) score; and iv. Leukocyte receptor complex (LCR) SNPs; c. If the one or more immunogenetic biomarkers of step b are detected in the biological sample, once viral suppression is achieved, the viral suppressive treatment is immediately discontinued, preferably, the viral suppressive treatment is performed after 2 years of treatment suspend; or If the immunogenetic biomarker of step b is not detected in the biological sample, the viral suppression therapy is continued, even after viral suppression is achieved, and/or an additional or different viral suppression therapy is administered to the individual.

在另一個一般態樣中，本申請案提供一種病毒抑制治療，特別是包含核苷酸或核苷類似物(NUC)之病毒抑制治療，更特別是包含選自由替諾福韋、恩替卡韋、拉米夫定、阿德福韋及替比夫定組成之群之NUC之病毒抑制治療，其用於治療有需要個體中慢性B型肝炎病毒(CHB)感染，其中該治療包括： a. 對該個體投與病毒抑制治療以治療CHB感染； b. 偵測從該個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i. 人類白血球抗原(HLA)對偶基因； ii. 一或多個HLA-C單核苷酸多型性(SNP)； iii. HLA演化多樣性(HED)分數；及 iv. 白血球受體複合物(LCR) SNP； c. 當個體中CHB感染得以抑制時，中止病毒抑制治療，及 d. 若在生物樣本中未偵測到免疫遺傳生物標記，則在中止之後少於兩年對該個體投與病毒抑制治療或另一病毒抑制治療。 In another general aspect, the application provides a viral suppressive therapy, particularly a viral suppressive therapy comprising a nucleotide or nucleoside analog (NUC), more particularly a viral suppressive therapy comprising a group selected from tenofovir, entecavir, Viral suppression therapy for NUC of the group consisting of mivudine, adefovir and telbivudine for the treatment of chronic hepatitis B virus (CHB) infection in individuals in need thereof, wherein the therapy comprises: a. administering to the individual viral suppressive therapy to treat CHB infection; b. Detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. Human leukocyte antigen (HLA) pair genes; ii. One or more HLA-C single nucleotide polytypes (SNPs); iii. HLA Evolutionary Diversity (HED) score; and iv. Leukocyte receptor complex (LCR) SNPs; c. Discontinue viral suppression therapy when CHB infection is suppressed in the individual, and d. If no immunogenetic biomarker is detected in the biological sample, administer viral suppressive therapy or another viral suppressive therapy to the individual less than two years after discontinuation.

如本文所用，當免疫遺傳生物標記係HED分數時，「偵測從個體獲得的生物樣本中CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在」係指判定生物樣本中之HED分數。As used herein, when the immunogenetic biomarker is the HED score, "detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from an individual" refers to determining the HED score in the biological sample .

在某些實施例中，免疫遺傳生物標記包含HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在。HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在預測病毒抑制治療中止之後復發的低機率，較佳係病毒學復發的低機率。HLA對偶基因B*51或C*15的不存在或HLA對偶基因C*07的存在預測病毒抑制治療中止之後復發的高機率，較佳係病毒學復發的高機率。在其他實施例中，HLA對偶基因C*15係C*15:02及HLA對偶基因C*07係C*07:02。In certain embodiments, the immunogenetic biomarker comprises the presence of HLA counterpart B*51 or C*15 or the absence of HLA counterpart C*07. The presence of the HLA counterpart B*51 or C*15 or the absence of the HLA counterpart C*07 predicts a low chance of relapse after cessation of viral suppressive therapy, preferably a low chance of virological relapse. The absence of the HLA counterpart B*51 or C*15 or the presence of the HLA counterpart C*07 predicts a high probability of relapse, preferably virological relapse, after cessation of viral suppressive therapy. In other embodiments, the HLA counterpart C*15 is C*15:02 and the HLA counterpart C*07 is C*07:02.

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之HLA-C SNP：rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、rs9264039及rs3868078或其互補序列。本文所描述的HLA-C SNP的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的HLA-C SNP的不存在預測在病毒抑制治療中止之後復發的高機率。In certain embodiments, the immunogenetic biomarker comprises an HLA-C SNP selected from the group consisting of: rs2394952, rs3130542, rs2894202, rs9264523, rs1049281, rs9264643, rs1130838, rs2394888, AX-83089411, rs2308622, rs91640416, rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、 rs9264039 and rs3868078 or their complements. The presence of the HLA-C SNPs described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the HLA-C SNPs described herein predicts a high probability of relapse following discontinuation of viral suppressive therapy.

在其他實施例中，HLA-C SNP係選自由以下組成之群： rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750或其互補序列。本文所描述的HLC-C SNP可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。在其他實施例中，HLA-C SNP係選自由以下組成之群： rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、 rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750或其互補序列。 The HLC-C SNPs described herein can be used to predict the probability of virological relapse following discontinuation of virological suppression therapy for CHB.

在其他實施例中，HLA-C SNP係選自由s4084090、rs9264127、rs9264039及rs3868078或其互補序列組成之群。本文所描述的HLC-C SNP可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。In other embodiments, the HLA-C SNPs are selected from the group consisting of s4084090, rs9264127, rs9264039 and rs3868078 or their complements. The HLC-C SNPs described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該免疫遺傳生物標記包含至少一個大於選自下表之臨限值之HED分數： HLA 區域 HLA 基因 變數 臨限值 平均HLA I類 HLA-A HED_HLA_A_CAT_VR 3.88 平均HLA I類 HLA-B HED_HLA_B_CAT_VR 9.37 平均HLA I類 HLA-C HED_HLA_C_CAT_VR 0.00 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_VR 8.69 平均HLA II類 HLA-DPB1 HED_HLA_P_CAT_VR 2.21 平均HLA II類 HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_VR 12.68 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_VR 7.55 平均HLA I類 HLA-A HED_HLA_A_CAT_CR 3.88 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_CR 7.67 平均HLA I類 HLA-C HED_HLA_C_CAT_SCR 7.37 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_SCR 7.61 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_SCR 8.21 In certain embodiments, the immunogenetic biomarker comprises at least one HED score greater than a threshold value selected from the following table: HLA region HLA gene variable Threshold value Average HLA class I HLA-A HED_HLA_A_CAT_VR 3.88 Average HLA class I HLA-B HED_HLA_B_CAT_VR 9.37 Average HLA class I HLA-C HED_HLA_C_CAT_VR 0.00 Average HLA class I MEAN_MHCI HED_MEANI_CAT_VR 8.69 Average HLA class II HLA-DPB1 HED_HLA_P_CAT_VR 2.21 Average HLA class II HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_VR 12.68 Average HLA class II MEAN_MHCII HED_MEANII_CAT_VR 7.55 Average HLA class I HLA-A HED_HLA_A_CAT_CR 3.88 Average HLA class II MEAN_MHCII HED_MEANII_CAT_CR 7.67 Average HLA class I HLA-C HED_HLA_C_CAT_SCR 7.37 Average HLA class I MEAN_MHCI HED_MEANI_CAT_SCR 7.61 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 Average HLA class II MEAN_MHCII HED_MEANII_CAT_SCR 8.21

本文所描述的HED分數的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的HED分數的不存在預測在病毒抑制治療中止之後復發的高機率。The presence of the HED scores described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the HED scores described herein predicts a high chance of relapse after cessation of viral suppressive therapy.

在其他實施例中，HED分數係選自由HED HLA-A大於3.88之值、HED HLA-B大於9.37之值、HED HLA-C大於0.00之值、平均HED HLA I類大於8.69之值、HED HLA-DPB1大於2.21之值、HED HLA-DQB1大於11.98之值、HED HLA-DRB1大於12.68之值及平均HED HLA II類大於7.55之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。In other embodiments, the HED score is selected from the group consisting of HED HLA-A greater than 3.88, HED HLA-B greater than 9.37, HED HLA-C greater than 0.00, average HED HLA class I value greater than 8.69, HED HLA - A group consisting of a value of DPB1 greater than 2.21, a value of HED HLA-DQB1 greater than 11.98, a value of HED HLA-DRB1 greater than 12.68 and a value of average HED HLA class II greater than 7.55. The HED scores described herein can be used to predict the probability of virological relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，HED分數係選自由HED HLA-A大於3.88之值及平均HED HLA II類大於7.67之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。In other embodiments, the HED score is selected from the group consisting of a HED HLA-A value greater than 3.88 and a mean HED HLA class II value greater than 7.67. The HED scores described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，HED分數係選自由HED HLA-C大於7.37之值、平均HED HLA I類大於7.61之值、HED HLA-DRB1大於14.16之值及平均HED HLA II類大於8.21之值組成之群。本文所描述的HED分數可用於預測CHB的病毒抑制治療中止之後持續臨床反應的機率。In other embodiments, the HED score is selected from the group consisting of HED HLA-C greater than 7.37, mean HED HLA class I greater than 7.61, HED HLA-DRB1 greater than 14.16, and mean HED HLA class II greater than 8.21 group. The HED scores described herein can be used to predict the probability of sustained clinical response after discontinuation of viral suppressive therapy for CHB.

在某些實施例中，免疫遺傳生物標記包含選自由以下組成之群之LCR SNP：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。本文所描述的LCR SNP的存在預測在病毒抑制治療中止之後復發的低機率。本文所描述的LCR SNP的不存在預測在病毒抑制治療中止之後復發的高機率。In certain embodiments, the immunogenetic biomarker comprises an LCR SNP selected from the group consisting of: rs10426302, rs59537494, rs28366008, rs36625, rs635608, rs7595, rs731170, rs28513, rs12459334, rs11666535, rs4806807, rs39084367, rs39084367 rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、 rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、 rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列。 The presence of the LCR SNPs described herein predicts a low chance of relapse following discontinuation of viral suppressive therapy. The absence of the LCR SNPs described herein predicts a high probability of relapse following discontinuation of viral suppressive therapy.

在其他實施例中，LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627或其互補序列。本文所描述的LCR SNP可用於預測CHB的病毒抑制治療中止之後病毒學復發的機率。在其他實施例中，LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、 rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、 rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627或其互補序列。 The LCR SNPs described herein can be used to predict the probability of virological relapse following discontinuation of viral suppressive therapy for CHB.

在其他實施例中，LCR SNP係選自由rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598或其互補序列組成之群。本文所描述的LCR SNP可用於預測CHB的病毒抑制治療中止之後臨床復發的機率。在其他實施例中，LCR SNP係選自由rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851 , rs622941 and rs60690598 or a group consisting of their complementary sequences. The LCR SNPs described herein can be used to predict the probability of clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施方案中，該病毒抑制治療進一步包括偵測生物樣本中一或多個選自由以下組成之群之HLA-C對偶基因的存在：rs2394952中之對偶基因A、rs3130542中之對偶基因G、rs2894202中之對偶基因G、rs9264523中之對偶基因A、rs1049281中之對偶基因C、rs9264643中之對偶基因A、rs1130838中之對偶基因A、rs2394888中之對偶基因G、AX-83089411中之對偶基因T、rs2308622中之對偶基因C、rs9264416中之對偶基因A、rs2001181中之對偶基因T、rs3132499中之對偶基因T、rs3130532中之對偶基因G、rs3130941中之對偶基因G、rs3130528中之對偶基因C、rs3134782中之對偶基因A、rs3134769中之對偶基因C、rs3130521中之對偶基因C、rs3130695中之對偶基因G、rs3130685中之對偶基因T、rs2524119中之對偶基因C、rs3130527中之對偶基因C、rs2894186中之對偶基因C、rs3130439中之對偶基因A、rs3095254中之對偶基因G、rs9264189中之對偶基因C、rs2394943中之對偶基因C、rs9394047中之對偶基因C、rs3130948中之對偶基因T、rs9368666中之對偶基因G、rs3130942中之對偶基因T、rs3130688中之對偶基因T、rs3130536中之對偶基因G、rs3134750中之對偶基因G、rs4084090中之對偶基因G、rs9264127中之對偶基因G、rs9264039中之對偶基因A及rs3868078中之對偶基因T或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的復發。In certain embodiments, the viral suppression therapy further comprises detecting the presence of one or more HLA-C counterpart genes selected from the group consisting of: counterpart gene A in rs2394952, counterpart gene G in rs3130542 in the biological sample , Dual gene G in rs2894202, dual gene A in rs9264523, dual gene C in rs1049281, dual gene A in rs9264643, dual gene A in rs1130838, dual gene G in rs2394888, dual gene in AX-83089411 T, the counterpart C in rs2308622, the counterpart A in rs9264416, the counterpart T in rs2001181, the counterpart T in rs3132499, the counterpart G in rs3130532, the counterpart G in rs3130941, the counterpart C in rs3130528 , Dual gene A in rs3134782, dual gene C in rs3134769, dual gene C in rs3130521, dual gene G in rs3130695, dual gene T in rs3130685, dual gene C in rs2524119, dual gene C in rs3130527, Dual gene C in rs2894186, dual gene A in rs3130439, dual gene G in rs3095254, dual gene C in rs9264189, dual gene C in rs2394943, dual gene C in rs9394047, dual gene T in rs3130948, dual gene rs9368666 Dual gene G in rs3130942, dual gene T in rs3130688, dual gene G in rs3130536, dual gene G in rs3134750, dual gene G in rs4084090, dual gene G in rs9264127, dual gene in rs9264039 The counterpart gene A and the counterpart gene T in rs3868078 or its complement. The HLA-C dual genes described herein are protective against relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施方案中，該病毒抑制治療進一步包括偵測生物樣本中一或多個選自由以下組成之群之HLA-C對偶基因的存在：rs2394952中之對偶基因A、rs3130542中之對偶基因G、rs2894202中之對偶基因G、rs9264523中之對偶基因A、rs1049281中之對偶基因C、rs9264643中之對偶基因A、rs1130838中之對偶基因A、rs2394888中之對偶基因G、AX-83089411中之對偶基因T、rs2308622中之對偶基因C、rs9264416中之對偶基因A、rs2001181中之對偶基因T、rs3132499中之對偶基因T、rs3130532中之對偶基因G、rs3130941中之對偶基因G、rs3130528中之對偶基因C、rs3134782中之對偶基因A、rs3134769中之對偶基因C、rs3130521中之對偶基因C、rs3130695中之對偶基因G、rs3130685中之對偶基因T、rs2524119中之對偶基因C、rs3130527中之對偶基因C、rs2894186中之對偶基因C、rs3130439中之對偶基因A、rs3095254中之對偶基因G、rs9264189中之對偶基因C、rs2394943中之對偶基因C、rs9394047中之對偶基因C、rs3130948中之對偶基因T、rs9368666中之對偶基因G、rs3130942中之對偶基因T、rs3130688中之對偶基因T、rs3130536中之對偶基因G及rs3134750中之對偶基因G或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的病毒學復發。In certain embodiments, the viral suppression therapy further comprises detecting the presence of one or more HLA-C counterpart genes selected from the group consisting of: counterpart gene A in rs2394952, counterpart gene G in rs3130542 in the biological sample , Dual gene G in rs2894202, dual gene A in rs9264523, dual gene C in rs1049281, dual gene A in rs9264643, dual gene A in rs1130838, dual gene G in rs2394888, dual gene in AX-83089411 T, the counterpart C in rs2308622, the counterpart A in rs9264416, the counterpart T in rs2001181, the counterpart T in rs3132499, the counterpart G in rs3130532, the counterpart G in rs3130941, the counterpart C in rs3130528 , Dual gene A in rs3134782, dual gene C in rs3134769, dual gene C in rs3130521, dual gene G in rs3130695, dual gene T in rs3130685, dual gene C in rs2524119, dual gene C in rs3130527, Dual gene C in rs2894186, dual gene A in rs3130439, dual gene G in rs3095254, dual gene C in rs9264189, dual gene C in rs2394943, dual gene C in rs9394047, dual gene T in rs3130948, dual gene rs9368666 The counterpart G in rs3130942, the counterpart T in rs3130688, the counterpart G in rs3130536, and the counterpart G in rs3134750 or their complements. The HLA-C dual genes described herein are protective against virological relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該病毒抑制治療進一步包括偵測生物樣本中一或多個選自由以下組成之群之HLA-C對偶基因的存在：rs4084090中之對偶基因G、rs9264127中之對偶基因G、rs9264039中之對偶基因A及rs3868078中之對偶基因T或其互補序列。本文所描述的HLA-C對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的臨床復發。In certain embodiments, the viral suppressive therapy further comprises detecting the presence of one or more HLA-C counterpart genes selected from the group consisting of: counterpart G in rs4084090, counterpart G in rs9264127 in the biological sample , the counterpart gene A in rs9264039 and the counterpart gene T in rs3868078 or its complement. The HLA-C dual genes described herein are protective against clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該病毒抑制治療進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs10426302中之對偶基因A、rs59537494中之對偶基因C、rs28366008中之對偶基因C、rs36625中之對偶基因G、rs635608中之對偶基因T、rs7595中之對偶基因C、rs731170中之對偶基因A、rs28513中之對偶基因A、rs12459334中之對偶基因T、rs11666535中之對偶基因T、rs4806807中之對偶基因T、rs11084367中之對偶基因A、rs39714中之對偶基因G、rs1654474中之對偶基因C、rs12462907中之對偶基因C、rs775893中之對偶基因G、rs10416527中之對偶基因A、rs4441391中之對偶基因A、rs40167中之對偶基因A、rs11084339中之對偶基因A、rs775875中之對偶基因A、rs2304225中之對偶基因C、rs4077076中之對偶基因A、rs4442924中之對偶基因A、rs4806527中之對偶基因A、rs12608979中之對偶基因C、COSV52557220之rs3765013中之對偶基因A、rs12462181中之對偶基因T、COSV52550169之rs2075731中之對偶基因T、rs12608988中之對偶基因G、rs190480734中之對偶基因G、rs1654452中之對偶基因G、rs11879415中之對偶基因T、rs653560中之對偶基因G、rs11084387中之對偶基因G、rs11672111中之對偶基因G、rs10424969中之對偶基因T、rs77389424中之對偶基因T、CM1111041之rs3745902中之對偶基因C、rs11672983中之對偶基因G、rs17836364中之對偶基因A、rs34549987中之對偶基因C、rs11668526中之對偶基因T、rs11667105中之對偶基因G、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs73618328中之對偶基因C、rs270785中之對偶基因C、rs76522818中之對偶基因C、rs62131745中之對偶基因C、rs2241384中之對偶基因G、rs1325158中之對偶基因T、rs10500318中之對偶基因G、rs3816051中之對偶基因T、rs34508934中之對偶基因C、rs12460627中之對偶基因G、rs11667812中之對偶基因C、rs12974194中之對偶基因C、rs17836364中之對偶基因A、rs11669431中之對偶基因C、rs12984962中之對偶基因C、rs1761462中之對偶基因T、rs4806464中之對偶基因C、rs34190750中之對偶基因C、rs28681595中之對偶基因T、rs12610675中之對偶基因G、rs12463051中之對偶基因A、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs41275824中之對偶基因C、rs2241384中之對偶基因G、rs12983338中之對偶基因T、rs272408中之對偶基因T、rs10412569中之對偶基因G、AX-3232794851中之對偶基因T、rs622941中之對偶基因G及rs60690598中之對偶基因C或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的復發。In certain embodiments, the viral suppressive therapy further comprises detecting the presence in the biological sample of one or more LCR counterpart genes selected from the group consisting of: counterpart A in rs10426302, counterpart C in rs59537494, rs28366008 Dual gene C in rs36625, dual gene G in rs635608, dual gene C in rs7595, dual gene A in rs731170, dual gene A in rs28513, dual gene T in rs12459334, dual gene in rs11666535 The counterpart T in rs4806807, the counterpart A in rs11084367, the counterpart G in rs39714, the counterpart C in rs1654474, the counterpart C in rs12462907, the counterpart G in rs775893, the counterpart G in rs10416527 Dual gene A, dual gene A in rs4441391, dual gene A in rs40167, dual gene A in rs11084339, dual gene A in rs775875, dual gene C in rs2304225, dual gene A in rs4077076, dual gene in rs4442924 Gene A, paired gene A in rs4806527, paired gene C in rs12608979, paired gene A in rs3765013 of COSV52557220, paired gene T in rs12462181, paired gene T in rs2075731 of COSV52550169, paired gene G in rs12608988, paired gene G in rs13904807 Dual gene G in rs1654452, dual gene G in rs11879415, dual gene G in rs653560, dual gene G in rs11084387, dual gene G in rs11672111, dual gene T in rs10424969, dual gene in rs77389424 Gene T of CM1111041, Gene C of rs3745902 of CM1111041, Gene G of rs11672983, Gene A of rs17836364, Gene C of rs34549987, Gene T of rs11668526, Gene G of rs11667105, Gene G of rs1749282 Dual gene G in rs1654660, dual gene C in rs73618328, dual gene C in rs270785, dual gene C in rs76522818, dual gene C in rs62131745, dual gene G in rs2241384, dual gene in rs1325158 The counterpart gene T in rs10500318, the counterpart gene G in rs10500318, Dual gene T in rs3816051, dual gene C in rs34508934, dual gene G in rs12460627, dual gene C in rs11667812, dual gene C in rs12974194, dual gene A in rs17836364, dual gene C in rs11669431, dual gene C in rs12984962 Dual gene C in rs1761462, dual gene C in rs4806464, dual gene C in rs34190750, dual gene T in rs28681595, dual gene G in rs12610675, dual gene A in rs12463051, dual gene in rs1749282 Dual gene G in rs1654660, dual gene C in rs41275824, dual gene G in rs2241384, dual gene T in rs12983338, dual gene T in rs272408, dual gene G in rs10412569, AX-3232794851 The counterpart gene T in rs622941, the counterpart gene G in rs622941, and the counterpart gene C in rs60690598 or their complements. The LCR dual genes described herein are protective against relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該病毒抑制治療進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs10426302中之對偶基因A、rs59537494中之對偶基因C、rs28366008中之對偶基因C、rs36625中之對偶基因G、rs635608中之對偶基因T、rs7595中之對偶基因C、rs731170中之對偶基因A、rs28513中之對偶基因A、rs12459334中之對偶基因T、rs11666535中之對偶基因T、rs4806807中之對偶基因T、rs11084367中之對偶基因A、rs39714中之對偶基因G、rs1654474中之對偶基因C、rs12462907中之對偶基因C、rs775893中之對偶基因G、rs10416527中之對偶基因A、rs4441391中之對偶基因A、rs40167中之對偶基因A、rs11084339中之對偶基因A、rs775875中之對偶基因A、rs2304225中之對偶基因C、rs4077076中之對偶基因A、rs4442924中之對偶基因A、rs4806527中之對偶基因A、rs12608979中之對偶基因C、COSV52557220之rs3765013中之對偶基因A、rs12462181中之對偶基因T、COSV52550169之rs2075731中之對偶基因T、rs12608988中之對偶基因G、rs190480734中之對偶基因G、rs1654452中之對偶基因G、rs11879415中之對偶基因T、rs653560中之對偶基因G、rs11084387中之對偶基因G、rs11672111中之對偶基因G、rs10424969中之對偶基因T、rs77389424中之對偶基因T、CM1111041之rs3745902中之對偶基因C、rs11672983中之對偶基因G、rs17836364中之對偶基因A、rs34549987中之對偶基因C、rs11668526中之對偶基因T、rs11667105中之對偶基因G、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs73618328中之對偶基因C、rs270785中之對偶基因C、rs76522818中之對偶基因C、rs62131745中之對偶基因C、rs2241384中之對偶基因G、rs1325158中之對偶基因T、rs10500318中之對偶基因G、rs3816051中之對偶基因T、rs34508934中之對偶基因C及rs12460627中之對偶基因G或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的病毒學復發。In certain embodiments, the viral suppressive therapy further comprises detecting the presence in the biological sample of one or more LCR counterpart genes selected from the group consisting of: counterpart A in rs10426302, counterpart C in rs59537494, rs28366008 Dual gene C in rs36625, dual gene G in rs635608, dual gene C in rs7595, dual gene A in rs731170, dual gene A in rs28513, dual gene T in rs12459334, dual gene in rs11666535 The counterpart T in rs4806807, the counterpart A in rs11084367, the counterpart G in rs39714, the counterpart C in rs1654474, the counterpart C in rs12462907, the counterpart G in rs775893, the counterpart G in rs10416527 Dual gene A, dual gene A in rs4441391, dual gene A in rs40167, dual gene A in rs11084339, dual gene A in rs775875, dual gene C in rs2304225, dual gene A in rs4077076, dual gene in rs4442924 Gene A, paired gene A in rs4806527, paired gene C in rs12608979, paired gene A in rs3765013 of COSV52557220, paired gene T in rs12462181, paired gene T in rs2075731 of COSV52550169, paired gene G in rs12608988, paired gene G in rs13904807 Dual gene G in rs1654452, dual gene G in rs11879415, dual gene G in rs653560, dual gene G in rs11084387, dual gene G in rs11672111, dual gene T in rs10424969, dual gene in rs77389424 Gene T of CM1111041, Gene C of rs3745902 of CM1111041, Gene G of rs11672983, Gene A of rs17836364, Gene C of rs34549987, Gene T of rs11668526, Gene G of rs11667105, Gene G of rs1749282 Dual gene G in rs1654660, dual gene C in rs73618328, dual gene C in rs270785, dual gene C in rs76522818, dual gene C in rs62131745, dual gene G in rs2241384, dual gene in rs1325158 The counterpart gene T in rs10500318, the counterpart gene G in rs10500318, The counterpart gene T in rs3816051, the counterpart gene C in rs34508934 and the counterpart gene G in rs12460627 or their complements. The LCR dual genes described herein are protective against virological relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，該病毒抑制治療進一步包括偵測生物樣本中一或多個選自由以下組成之群之LCR對偶基因的存在：rs11667812中之對偶基因C、rs12974194中之對偶基因C、rs17836364中之對偶基因A、rs11669431中之對偶基因C、rs12984962中之對偶基因C、rs1761462中之對偶基因T、rs4806464中之對偶基因C、rs34190750中之對偶基因C、rs28681595中之對偶基因T、rs12610675中之對偶基因G、rs12463051中之對偶基因A、rs1749282中之對偶基因G、rs1654660中之對偶基因A、rs41275824中之對偶基因C、rs2241384中之對偶基因G、rs12983338中之對偶基因T、rs272408中之對偶基因T、rs10412569中之對偶基因G、AX-3232794851中之對偶基因T、rs622941中之對偶基因G及rs60690598中之對偶基因C或其互補序列。本文所描述的LCR對偶基因可保護性抵抗CHB之病毒抑制治療的中止之後的臨床復發。In certain embodiments, the viral suppression therapy further comprises detecting the presence of one or more LCR counterpart genes in the biological sample selected from the group consisting of: counterpart C in rs11667812, counterpart C in rs12974194, rs17836364 Gene A in rs11669431, C in rs12984962, T in rs1761462, C in rs4806464, C in rs34190750, T in rs28681595, T in rs12610675 Gene G in rs12463051, Gene A in rs1749282, Gene A in rs1654660, Gene C in rs41275824, Gene G in rs2241384, Gene T in rs12983338, Gene T in rs272408 Dual gene T, dual gene G in rs10412569, dual gene T in AX-3232794851, dual gene G in rs622941 and dual gene C in rs60690598 or their complementary sequences. The LCR dual genes described herein are protective against clinical relapse following discontinuation of viral suppressive therapy for CHB.

在某些實施例中，CHB感染之病毒抑制治療係NUC治療。該NUC可為替諾福韋、恩替卡韋、拉米夫定、阿德福韋或替比夫定。In certain embodiments, the viral suppressive therapy for CHB infection is NUC therapy. The NUC can be tenofovir, entecavir, lamivudine, adefovir, or telbivudine.

在某些實施例中，CHB感染之病毒抑制治療係NUC治療。該NUC可為替諾福韋、恩替卡韋、拉米夫定、阿德福韋或替比夫定。In certain embodiments, the viral suppressive therapy for CHB infection is NUC therapy. The NUC can be tenofovir, entecavir, lamivudine, adefovir, or telbivudine.

在某些實施例中，使用熟習此項技術者已知的任何方法來判定生物樣本中一或多個免疫遺傳生物標記的存在或不存在。In certain embodiments, the presence or absence of one or more immunogenetic biomarkers in a biological sample is determined using any method known to those skilled in the art.

在某些實施例中，該個體在病毒抑制治療之後的一年、兩年、三年或四年或其間的任何時間時或之後達成HBV DNA ＜ 60 IU/mL、ALT ＜ 80 U/L或HBeAg陰性。在其他實施例中，該個體然後中止病毒抑制治療。In certain embodiments, the individual achieves HBV DNA < 60 IU/mL, ALT < 80 U/L, or at or after one year, two years, three years, or four years, or any time in between, following viral suppression therapy HBeAg negative. In other embodiments, the individual then discontinues viral suppression therapy.

在其他實施例中，個體在病毒抑制治療中止之後3個月、6個月、12個月、18個月、24個月或36個月其間的任何時間時或之後沒有病毒學復發或臨床復發，且其中該病毒學復發經識別為HBV DNA ≥ 2000 IU/ml或HBeAg陽性，及該臨床復發經識別為i) HBV DNA ≥ 2000 IU/ml或HBeAg陽性，且ii) ALT ≥ 80 U/L。In other embodiments, the subject has no virological or clinical relapse at or after 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months after cessation of viral suppression therapy , and wherein the virological relapse is identified as HBV DNA ≥ 2000 IU/ml or HBeAg positive, and the clinical relapse is identified as i) HBV DNA ≥ 2000 IU/ml or HBeAg positive, and ii) ALT ≥ 80 U/L .

在某些實施例中，樣本係組織樣本、細胞樣本或血液樣本。較佳地，樣本係血液樣本。In certain embodiments, the sample is a tissue sample, a cell sample, or a blood sample. Preferably, the sample is a blood sample.

在某些實施例中，樣本係在病毒抑制治療之前、期間或之後獲得。In certain embodiments, the sample is obtained before, during, or after viral suppressive therapy.

在某些實施例中，CHB感染在病毒抑制治療中止之時得以抑制。在一個實施例中，當個體在病毒抑制治療之後的一年、兩年、三年或四年或其間的任何時間時或之後達成HBV DNA ＜ 60 IU/mL、ALT ＜ 80 U/L或HBeAg陰性時，個體中止病毒抑制治療。較佳地，個體在病毒抑制治療中止時達成HBsAg ＜ 100 IU/mL。In certain embodiments, CHB infection is suppressed upon discontinuation of viral suppressive therapy. In one embodiment, when the individual achieves HBV DNA < 60 IU/mL, ALT < 80 U/L or HBeAg at or after one, two, three or four years or any time in between following viral suppression therapy When negative, the subject discontinued viral suppression therapy. Preferably, the individual achieves HBsAg < 100 IU/mL at the time of discontinuation of viral suppressive therapy.

在某些實施例中，該病毒抑制治療進一步包括在病毒抑制治療中止之後的3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後測定HBV DNA、ALT及HBsAg。In certain embodiments, the viral suppressive therapy further comprises at 3 months, 6 months, 12 months, 18 months, 24 months or 36 months or any time in between after discontinuation of the viral suppressive therapy or HBV DNA, ALT and HBsAg were then determined.

在某些實施例中，個體在中止病毒抑制治療之後的3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後沒有病毒學復發，且病毒學復發經識別為HBV DNA ≥ 2000 IU/ml或HBeAg陽性。In certain embodiments, the subject has no virological relapse at or after 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, or any time in between, after discontinuation of viral suppressive therapy , and virological recurrence was identified as HBV DNA ≥ 2000 IU/ml or HBeAg positive.

在某些實施例中，個體在中止病毒抑制治療之後的3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後沒有臨床復發，且臨床復發經識別為i) HBV DNA ≥ 2000 IU/ml或HBeAg陽性，且ii) ALT ≥ 80 U/L。In certain embodiments, the subject is free of clinical relapse at or after 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months, or any time in between, after discontinuation of viral suppression therapy, And clinical relapse was identified as i) HBV DNA ≥ 2000 IU/ml or HBeAg positive, and ii) ALT ≥ 80 U/L.

有鑑於本揭示，可使用此項技術中已知或本文所描述之任何方法偵測SNP的存在。根據本申請案之實施例，SNP或對偶基因係藉由選自由以下組成之群之方法來判定：DNA定序、限制片段長度多型性(RFLP分析)、對偶基因特異性寡核苷酸(ASO)分析、變性/溫度梯度凝膠電泳(DGGE/TGGE)、單股構象多型性(SSCP)分析、雙去氧指紋分析(ddF)、焦磷酸定序分析、acycloprime分析、反向墨點轉漬、基因晶片(GeneChip)微陣列、動態對偶基因特異性雜交(DASH)、肽核酸(PNA)及鎖核酸(LNA)探針、TaqMan、分子信標、嵌入染料、FRET引子、AlphaScreen、SNPstream、遺傳位元分析(GBA)、多重微定序、SNaPshot、MassEXTEND、MassArray、GOOD檢定、微陣列微定序、陣列式引子延伸(APEX)、微陣列引子延伸、標籤陣列、經編碼之微球、模板導向併入(TDI)、螢光偏振、比色寡核苷酸連接檢定(OLA)、序列編碼OLA、微陣列連接、連接酶鏈反應、扣鎖(Padlock)探針、滾環擴增及侵入物(Invader)檢定。 實例 實例 1 ：與病毒學及臨床復發之初發及持續臨床反應相關聯之病毒學及宿主人類白血球抗原 (HLA) 分型印記的識別及評估 In view of the present disclosure, the presence of SNPs can be detected using any method known in the art or described herein. According to embodiments of the present application, SNPs or counterparts are determined by a method selected from the group consisting of DNA sequencing, restriction fragment length polymorphism (RFLP analysis), counterpart-specific oligonucleotides ( ASO) analysis, denaturing/temperature gradient gel electrophoresis (DGGE/TGGE), single-strand conformational polymorphism (SSCP) analysis, dideoxy fingerprint analysis (ddF), pyrosequencing analysis, acycloprime analysis, reverse ink dot analysis Transfection, GeneChip Microarray, Dynamic Dual Gene-Specific Hybridization (DASH), Peptide Nucleic Acid (PNA) and Locked Nucleic Acid (LNA) Probes, TaqMan, Molecular Beacons, Intercalating Dyes, FRET Primers, AlphaScreen, SNPstream , Genetic Bit Analysis (GBA), Multiplex Microsequencing, SNaPshot, MassEXTEND, MassArray, GOOD Assay, Microarray Microsequencing, Arrayed Primer Extension (APEX), Microarray Primer Extension, Tag Array, Encoded Microspheres , Template-Directed Incorporation (TDI), Fluorescence Polarization, Colorimetric Oligonucleotide Ligation Assay (OLA), Sequence-Encoded OLA, Microarray Ligation, Ligase Chain Reaction, Padlock Probes, Rolling Circle Amplification and Invader checks. EXAMPLES Example 1 : Identification and assessment of virological and host human leukocyte antigen (HLA) typing signatures associated with virological and clinical relapse onset and ongoing clinical responses

本研究之目標係評估病毒學及宿主人類白血球抗原(HLA)分型印記，該印記可與直接抗病毒治療中止之後慢性B型肝炎(CHB)患者中復發及持續反應相關聯。 材料及方法 The objective of this study was to evaluate the virological and host human leukocyte antigen (HLA) typing signature that can be associated with relapse and persistent response in chronic hepatitis B (CHB) patients after discontinuation of direct antiviral therapy. Materials and Methods

患者及研究設計：在臺灣的該多中心前瞻性研究中，242名CHB患者入選而在其最少3年治療方案的最後半年使用直接抗病毒劑。其中，47例因協定違反、篩選失敗、無法進行隨訪、個體退出、使用免疫相關療法或治療中(on-treatment)臨床復發而被排除。另外14例被排除，因為分析要求患者在最後一次治療中(on treatment)就診時為B型肝炎e抗原(HBeAg)陰性、肝炎病毒(HBV) DNA ＜ 60 IU/mL及丙胺酸轉胺酶(ALT) ＜ 80 U/L，其餘186名患者符合分析資格。PATIENTS AND STUDY DESIGN: In this multicenter prospective study in Taiwan, 242 CHB patients were enrolled and used direct antiviral agents during the last half of their minimum 3-year treatment regimen. Of these, 47 were excluded due to protocol violation, screening failure, inability to follow up, individual withdrawal, use of immune-related therapy, or on-treatment clinical relapse. An additional 14 were excluded because the analysis required patients to be hepatitis B e-antigen (HBeAg) negative, hepatitis virus (HBV) DNA < 60 IU/mL and alanine aminotransferase (ALT) at the last on treatment visit. ALT) < 80 U/L, and the remaining 186 patients were eligible for analysis.

在評估病毒學及臨床復發中，患者在治療中止之後進行追蹤長達兩年，限制條件為不重新開始治療。病毒學復發定義為HBV DNA ≥ 2000 IU/mL。除了病毒學復發外，臨床復發定義為ALT量 ≥ 2x ULN。如果在治療停止之後的整個隨訪期期間沒有發生臨床及病毒學復發，則患者表示為持續臨床反應者。In assessing virological and clinical relapse, patients were followed for up to two years after treatment discontinuation, with the restriction that treatment was not restarted. Virological relapse was defined as HBV DNA ≥ 2000 IU/mL. In addition to virological relapse, clinical relapse was defined as ALT volume ≥ 2x ULN. Patients were designated as sustained clinical responders if no clinical and virological relapse occurred throughout the follow-up period following treatment cessation.

血清學：在治療中期間，在3個時間點收集血液樣本，最後一個在治療的最後一天前後收集。在治療中止之後的隨訪期中，以3或6個月時間間隔收集另外血液樣本，限制條件為不重新開始治療。Serology: During the mid-treatment period, blood samples were collected at 3 time points, the last one around the last day of treatment. During the follow-up period following treatment discontinuation, additional blood samples were collected at 3 or 6 month intervals, with the proviso that treatment was not restarted.

HLA分型：各個體均藉由針對HLA I類區域(A、B及C基因)及HLA II類區域(DRB1及DQB1基因)進行Sanger定序加以HLA分型。II類區域中之DPB1基因藉由高解析度聚合酶鏈反應-基於序列之分型(PCR-SBT)方法1來表徵且藉由深度定序(TBG HLA DPB1分型套組，其含有DPB1基因座特異性引子)對顯示模糊性的21個樣本進行補充。使用Illumina Miseq v2 300定序擴增子且藉由Omixon Twin軟體分析該等擴增子以進行HLA基因型分析。HLA typing: Individuals were HLA typed by Sanger sequencing for HLA class I regions (A, B and C genes) and HLA class II regions (DRB1 and DQB1 genes). The DPB1 gene in the class II region was characterized by high-resolution polymerase chain reaction-sequence-based typing (PCR-SBT) method 1 and by deep sequencing (TBG HLA DPB1 typing panel containing the DPB1 gene locus-specific primers) complemented the 21 samples showing ambiguity. Amplicons were sequenced using Illumina Miseq v2 300 and analyzed by Omixon Twin software for HLA genotyping.

HLA對偶基因：對於I類及II類區域中的各基因，應用顯性模型(存在vs.不存在)及可加性模型(特異性對偶基因之0、1或2個複本視為連續變數)導出特異性對偶基因的存在。HLA dual genes: For each gene in the class I and class II regions, the dominant model (presence vs. absence) and the additive model (0, 1, or 2 copies of the specific dual gene are considered continuous variables) are applied Deriving the presence of specific dual genes.

HLA多樣性：對於各個體HLA分型化，獨立地對於HLA I類區域及HLA II類區域，HLA遺傳同合性已從每個基因座及每個對偶基因導出，比較各HLA基因之同合子與雜合子對偶基因之比例(針對各基因或基因座比較特異性對偶基因之零及兩個複本vs.一個複本) (Chowell等人，Science，2018，359: 582–7；Thursz等人，Nature Genetics 1997，17: 11–2)。HLA diversity: For each individual HLA typing, independently for HLA class I regions and HLA class II regions, HLA genetic homozygosity has been derived from each locus and each paired gene, and the homozygosity of each HLA gene is compared Ratio to heterozygous counterparts (compare zero and two copies vs. one copy of a specific counterpart for each gene or locus) (Chowell et al., Science, 2018, 359: 582-7; Thursz et al., Nature Genetics 1997, 17: 11–2).

HLA演化多樣性(HED)分數(一種對胺基酸組成之預測影響考慮在內的更複雜量度)已針對各患者導出作為每個基因分別跨所有HLA I類及II類基因(Arora等人，Molecular Biology and Evolution，2020，37: 639–50；Chowell等人，Nature Medicine，2019，25: 1715–20)的平均HED。特定而言，HLA對偶基因蛋白序列比對從ftp://ftp.ebi.ac.uk/pub/databases/ipd/imgt/hla/alignments/獲得且基於包含在IMGT/HLA數據庫(Release 3.40.0，2020-04-20) 6中之蛋白質序列。使用以下HLA蛋白基因座以供分析，對於HLA-I型：HLA-A、HLA-B及HLA-C；HLA-II型：HLA-DPB1、HLA-DRB1及HLA-DQB1。對於各HLA蛋白基因座，使用Ensembl數據庫蛋白質註釋來識別MHC抗原識別域之胺基酸坐標。整體而言，坐標涵蓋HLA-I型基因中之外顯子2及3及HLA-II型基因中之外顯子2及外顯子1之一部分。HLA Evolutionary Diversity (HED) scores, a more complex measure that takes into account predicted effects on amino acid composition, have been derived for each patient as each gene across all HLA class I and II genes separately (Arora et al., Molecular Biology and Evolution, 2020, 37: 639-50; Chowell et al, Nature Medicine, 2019, 25: 1715-20) mean HED. Specifically, HLA counterpart gene protein sequence alignments were obtained from ftp://ftp.ebi.ac.uk/pub/databases/ipd/imgt/hla/alignments/ and based on data contained in the IMGT/HLA database (Release 3.40.0 , 2020-04-20) protein sequences in 6. The following HLA protein loci were used for analysis, for HLA-type I: HLA-A, HLA-B and HLA-C; HLA-type II: HLA-DPB1, HLA-DRB1 and HLA-DQB1. For each HLA protein locus, the Ensembl database protein annotation was used to identify the amino acid coordinates of the MHC antigen recognition domain. Overall, the coordinates encompass exons 2 and 3 in HLA-type I genes and a portion of exon 2 and exon 1 in HLA-type II genes.

對於各個體及HLA基因座，提取使用4欄位HLA對偶基因識別碼的HLA基因型。4欄位HLA遺傳密碼然後用於在比對文檔中將對偶基因與相應蛋白質相匹配。就基因型中各對對偶基因而言，使用Grantham距離度量來衡量其功能距離(就經編碼之蛋白質而言)。Grantham距離係兩個胺基酸之間的定量成對距離。一對的距離考慮其物理化學特性(各胺基酸之生化組成、極性及體積)。一對序列之給定比對之Grantham整體發散度係藉由求和個別胺基酸對距離值且然後藉由將總和除以比對長度來計算。出於該分析之目的，僅考慮MHC結合域來計算差異。對於各患者，平均HED計算為針對HLA-I型之HLA-A、HLA-B及HLA-C及HLA-II型基因座之HLA-DPB1、HLA-DRB1及HLA-DQB1獲得的發散度之平均值。For each individual and HLA locus, HLA genotypes using the 4-column HLA paired gene identification code were extracted. The 4-column HLA genetic code is then used to match the counterpart gene to the corresponding protein in the alignment file. For each pair of dual genes in the genotype, the Grantham distance metric was used to measure the functional distance (in terms of encoded protein). The Grantham distance is the quantitative pairwise distance between two amino acids. The distance of a pair takes into account its physicochemical properties (biochemical composition, polarity and volume of each amino acid). The Grantham global divergence for a given alignment of a pair of sequences is calculated by summing the individual amino acid pair distance values and then by dividing the sum by the alignment length. For the purposes of this analysis, only the MHC binding domain was considered to calculate the difference. For each patient, the mean HED was calculated as the mean of the divergence obtained for HLA-A, HLA-B, and HLA-C of HLA-type I and HLA-DPB1, HLA-DRB1, and HLA-DQB1 for HLA-type II loci value.

除了導出的連續值外，HED分數亦分類為低及高階的二元變數以用於進一步分析。在關於病毒學及臨床復發之分析中，使用判定與復發相關之最佳截切點之survminer R包(surv_cutpoint函數)來導出分類臨限值。為了評估持續臨床反應，應用邏輯回歸，且對應於提供模型之ROC (接收器操作特性)曲線之最大AUC (曲線下面積)的值來選擇臨限值，除了治療結束HBsAg外亦包括分類HED分數變數。In addition to the derived continuous values, HED scores were also classified as low and high order binary variables for further analysis. In the analysis for virological and clinical relapse, classification thresholds were derived using the survminer R package (surv_cutpoint function) that determines the best cut-point associated with relapse. To assess sustained clinical response, logistic regression was applied and the threshold value was chosen corresponding to the value of the maximum AUC (area under the curve) of the ROC (receiver operating characteristic) curve providing the model, including categorical HED scores in addition to end-of-treatment HBsAg variable.

統計分析：連續變數以平均值±標準偏差呈現，分類變數以計數及百分比表示(參見下表1)。Statistical analysis: Continuous variables are presented as mean ± standard deviation, categorical variables are presented as counts and percentages (see Table 1 below).

藉由卡普蘭-邁爾曲線(圖1A及1B)評估治療停止之後的血清學及臨床復發之累積發病率。此外，應用Cox比例風險回歸分析(Yang等人，Biometrika，2005，92: 937–50)，獲得達成病毒學及臨床復發的時間的單變數及多變數模型(臨床及病毒學復發之模型擬合分別提供於表2a及表2b中；參見下表2a及2b)。Cumulative incidence of serological and clinical relapse after treatment cessation was assessed by Kaplan-Meier curves (Figures 1A and 1B). In addition, using Cox proportional hazards regression analysis (Yang et al., Biometrika, 2005, 92: 937-50), univariate and multivariate models of time to virological and clinical relapse (Model Fitting of Clinical and Virological Relapse) were obtained are provided in Table 2a and Table 2b, respectively; see Tables 2a and 2b below).

HLA數據之統計分析：使用Cox模型來評估HLA對偶基因(對於各基因座，以兩位及四位解析度)及發散度(遺傳同合性及HED分數，獨立地)與復發之初發之間的關聯(Harrell等人，JAMA: The Journal of the American Medical Association，1982，247: 2543)，Cox模型包括治療中最後一次就診時的HbsAg量(高(≥ 100 IU/mL) vs.低(＜ 100 IU/mL))及入選時的抗病毒治療(替諾福韋vs.恩替卡韋)作為主要效應。使用邏輯模型來評估HLA對偶基因(對於各基因座，以兩位及四位解析度)及發散度(遺傳同合性及HED分數，獨立地)與持續臨床反應(SCR)之間的關聯，邏輯模型包括治療中最後一次就診時的HbsAg量(高((≥ 100 IU/mL) vs. 低(＜ 100 IU/mL))作為主要效應。僅考慮所觀測小對偶基因頻率高於5%的HLA對偶基因。Statistical analysis of HLA data: Cox models were used to assess the relationship between HLA duality genes (at two- and four-digit resolution for each locus) and divergence (genetic identity and HED scores, independently) and onset of recurrence (Harrell et al., JAMA: The Journal of the American Medical Association, 1982, 247: 2543), the Cox model included HbsAg levels at the last visit during treatment (high (≥ 100 IU/mL) vs. low ( < 100 IU/mL)) and antiviral therapy at entry (tenofovir vs. entecavir) as the main effect. Logistic models were used to assess the association between HLA paired genes (at two- and four-digit resolution for each locus) and divergence (genetic identity and HED scores, independently) and sustained clinical response (SCR), The logistic model included the amount of HbsAg at the last visit during treatment (high ((≥ 100 IU/mL) vs. low (< 100 IU/mL)) as the main effect. Only those with observed minor paired gene frequencies above 5% were considered HLA dual genes.

將顯示錯誤發現率(FDR)低於10%之HLA對偶基因及HED分數視為顯著。FDR係根據分析(臨床復發、病毒學復發及持續臨床反應)及跨所有模型(可加性、顯性及同合子)計算。HLA counterpart genes and HED scores showing a false discovery rate (FDR) of less than 10% were considered significant. FDR was calculated based on analysis (clinical relapse, virological relapse and sustained clinical response) and across all models (additive, dominant and homozygous).

進一步探索與復發之初發顯著關聯之HLA標記，以便開發復發之早期初發之預測性(保護性)遺傳印記(基於HLA數據)。HLA markers significantly associated with onset of relapse were further explored in order to develop a predictive (protective) genetic signature (based on HLA data) of early onset of relapse.

對於臨床及病毒學復發，藉由AIC、BIC10及一致性(哈雷爾氏C指數(Harrell’s C-index))比較不同Cox比例風險回歸模型以評估與復發風險之關聯。此外，對於最相關模型，比較時間依賴性接收器操作特性(ROC)曲線(及相應曲線下面積(AUC))。For clinical and virological relapse, different Cox proportional hazards regression models were compared by AIC, BIC10 and concordance (Harrell's C-index) to assess the association with risk of relapse. In addition, time-dependent receiver operating characteristic (ROC) curves (and corresponding area under the curve (AUC)) were compared for the most relevant models.

對於持續臨床反應(SCR)，藉由AIC及BIC比較不同邏輯回歸模型以評估與長期治療反應的關聯。此外，對於最相關模型，比較ROC曲線(及相應AUC)。 結果 For sustained clinical response (SCR), different logistic regression models were compared by AIC and BIC to assess association with long-term treatment response. In addition, for the most relevant models, the ROC curves (and corresponding AUCs) were compared. result

研究群體：表1提供研究群體之臨床特性之綜述。總共101名患者完成本研究，對於83名患者，核苷(酸)類似物(NA)療法由於復發而重新開始。在研究期期間，一名患者死亡，及一名患者經診斷患有肝細胞癌。治療停止之後的隨訪時間在38至814天之範圍內，其中平均及中位隨訪時間分別為482天及637天。 表1. 研究群體之臨床特性 共變數 年齡(歲) 50.8 ± 11.3 性別 男性 142 (76.3%) 女性 44 (23.7%) 先前NA療法 是 64 (34.4%) 無 122 (65.6%) 基線HBeAg狀態 開始NA治療之前的陰性 142 (76.3%) NA療法期間獲得的陰性 44 (23.7%) 治療方案 恩替卡韋 106 (57.0%) 替諾福韋 65 (34.9%) 其他(拉米夫定、替比夫定、阿德福韋) 15 (8.1%) 長度NA療法(年數) 4.3 ± 1.9 治療中病毒抑制 無(全部偵測到HBV DNA) 26 (14.0%) 一致(HBV DNA均未偵測到) 38 (20.4%) 不一致(HBV DNA偵測到及未偵測到) 122 (65.6%) 治療結束HBV DNA 偵測到 96 (51.6%) 未偵測到 90 (48.4%) 治療結束HBsAg ＜ 100 IU/mL 39 (21.0%) ≥ 100 IU/mL 147 (79.0%) 治療結束HBsAg (log IU/mL) 5.6 ± 2.3 治療結束HBsAb (log mIU/mL) 0.16 ± 0.73 治療結束ALT (log U/L) 3.1 ± 0.47 治療結束AST (log U/L) 3.1 ± 0.29 1個月隨訪HBV DNA (log IU/mL) 5.5 ± 5.0 1個月隨訪HBsAg (log IU/mL) 5.5 ± 2.6 1個月隨訪ALT (log U/L) 3.3 ± 0.79 Study Population: Table 1 provides a summary of the clinical characteristics of the study population. A total of 101 patients completed the study, and for 83 patients, nucleoside (acid) analog (NA) therapy was restarted due to relapse. During the study period, one patient died and one patient was diagnosed with hepatocellular carcinoma. Follow-up times after treatment cessation ranged from 38 to 814 days, with mean and median follow-up times of 482 and 637 days, respectively. Table 1. Clinical characteristics of the study population covariate age) 50.8 ± 11.3 gender male 142 (76.3%) female 44 (23.7%) prior NA therapy Yes 64 (34.4%) none 122 (65.6%) Baseline HBeAg status Negative before starting NA therapy 142 (76.3%) Negatives obtained during NA therapy 44 (23.7%) treatment plan Entecavir 106 (57.0%) tenofovir 65 (34.9%) Others (lamivudine, telbivudine, adefovir) 15 (8.1%) Length of NA therapy (years) 4.3 ± 1.9 Viral suppression during therapy None (all HBV DNA detected) 26 (14.0%) Consistent (none of HBV DNA detected) 38 (20.4%) Inconsistent (HBV DNA detected and not detected) 122 (65.6%) End of treatment HBV DNA detected 96 (51.6%) not detected 90 (48.4%) End of treatment HBsAg < 100 IU/mL 39 (21.0%) ≥ 100 IU/mL 147 (79.0%) End of treatment HBsAg (log IU/mL) 5.6 ± 2.3 End of treatment HBsAb (log mIU/mL) 0.16 ± 0.73 End of treatment ALT (log U/L) 3.1 ± 0.47 End of treatment AST (log U/L) 3.1 ± 0.29 1-month follow-up HBV DNA (log IU/mL) 5.5 ± 5.0 1-month follow-up HBsAg (log IU/mL) 5.5 ± 2.6 1-month follow-up ALT (log U/L) 3.3 ± 0.79

在定群中包括的186名患者中，161名(86.6%)經歷病毒學復發(圖1A)，其中110名(59.2%)亦具有臨床復發(圖1B)。對於23名患者(12.4%)，於隨訪期觀測到持續臨床反應(請注意，死亡的患者及經診斷患有肝細胞癌的患者從持續臨床反應組排除)。51名(27.42%)患者具有病毒學復發而無臨床復發。在整個研究期中，11名喪失HBsAg。在彼等11名喪失HBsAg的患者中，7名亦被視為持續臨床反應者。三名在喪失HBsAg之前經歷病毒學復發，第四名係經診斷患有肝細胞癌且未被視為持續臨床反應者的患者。Of the 186 patients included in the cohort, 161 (86.6%) experienced virological relapse (Fig. 1A), of which 110 (59.2%) also had clinical relapse (Fig. 1B). For 23 patients (12.4%), sustained clinical responses were observed during the follow-up period (note that patients who died and those diagnosed with hepatocellular carcinoma were excluded from the sustained clinical response group). 51 (27.42%) patients had virological recurrence without clinical recurrence. Eleven lost HBsAg throughout the study period. Of their 11 patients who lost HBsAg, 7 were also considered to be sustained clinical responders. Three experienced virological relapse prior to loss of HBsAg, and the fourth was a patient diagnosed with hepatocellular carcinoma who was not considered a sustained clinical responder.

臨床復發：多變數Cox比例風險回歸分析顯示，老年(HR，1.02；95% CI，1.00–1.04；P = 0.02)、替諾福韋治療(與恩替卡韋治療相比) (HR，1.87；95% CI，1.26-2.78；P = 0.002)、及治療結束時的高HBsAg (HR，3.24；95% CI，1.75-6.01；P ＜ 0.001)增加臨床復發的風險且因此與臨床復發負面關聯(表2a)。使用100 IU/mL之HbsAg量作為臨限值來區分低及高的治療結束HbsAg，對應於89.09%敏感性及35.53%特異性。 表2a. 用於臨床復發之Cox比例風險回歸分析 共變數 單變數分析 多變數分析 HR (95% CI) P值 HR (95% CI) P值 年齡(歲) 1.01 (0.99-1.02) 0.43 1.02 (1.00-1.04) 0.02 性別(男性vs女性) 1.88 (1.15-3.09) 0.01 先前NA療法(是vs否) 1.26 (0.86-1.86) 0.24 基線HBeAg狀態(先前陰性vs治療期間) 1.35 (0.85-2.14) 0.2 治療方案 替諾福韋vs恩替卡韋 1.77 (1.19-2.62) 0.005 1.87 (1.26-2.78) 0.004 其他vs恩替卡韋 1.07 (0.51-2.25) 0.85 1.21 (0.58-2.57) 0.59 長度NA療法(年數) 0.96 (0.86-1.06) 0.39 治療中病毒抑制 不一致vs一致 1.46 (0.86-2.47) 0.16 無vs一致 1.71 (0.88-3.32) 0.12 治療結束時的HBV DNA (偵測vs未偵測) 1.39 (0.95-2.03) 0.09 治療結束時的HBsAg (≥ 100 IU/mL vs ＜ 100 IU/mL) 2.77 (1.51-5.05) ＜0.001 3.24 (1.75-6.01) ＜0.001 治療結束時的HBsAb (log mIU/mL) 0.86 (0.63-1.18) 0.35 治療結束時的ALT (log U/L) 1.04 (0.70-1.53) 0.85 治療結束時的AST (log U/L) 1.02 (0.54-1.91) 0.96 停止治療之後1個月時的HBV DNA (log IU/mL) 1.21 (1.15-1.27) ＜0.001 停止治療之後1個月時的ALT (log U/L) 2.19 (1.60-3.01) ＜0.001 停止治療之後1個月時的HBsAg (log IU/mL) 1.21 (1.08-1.35) ＜0.001 Clinical recurrence: Multivariate Cox proportional hazards regression analysis showed that older age (HR, 1.02; 95% CI, 1.00–1.04; P = 0.02), tenofovir treatment (compared with entecavir treatment) (HR, 1.87; 95%) CI, 1.26-2.78; P = 0.002), and high HBsAg at the end of treatment (HR, 3.24; 95% CI, 1.75-6.01; P < 0.001) increased the risk of, and therefore negatively associated with, clinical recurrence (Table 2a) ). A HbsAg level of 100 IU/mL was used as the threshold to differentiate between low and high end-of-treatment HbsAg, corresponding to 89.09% sensitivity and 35.53% specificity. Table 2a. Cox proportional hazards regression analysis for clinical recurrence covariate Univariate Analysis multivariate analysis HR (95% CI) P value HR (95% CI) P value age) 1.01 (0.99-1.02) 0.43 1.02 (1.00-1.04) 0.02 Gender (male vs female) 1.88 (1.15-3.09) 0.01 Prior NA therapy (yes vs no) 1.26 (0.86-1.86) 0.24 Baseline HBeAg status (previously negative vs during treatment) 1.35 (0.85-2.14) 0.2 treatment plan Tenofovir vs Entecavir 1.77 (1.19-2.62) 0.005 1.87 (1.26-2.78) 0.004 Other vs Entecavir 1.07 (0.51-2.25) 0.85 1.21 (0.58-2.57) 0.59 Length of NA therapy (years) 0.96 (0.86-1.06) 0.39 Viral suppression during therapy inconsistent vs consistent 1.46 (0.86-2.47) 0.16 None vs Consistent 1.71 (0.88-3.32) 0.12 HBV DNA at the end of treatment (detected vs undetected) 1.39 (0.95-2.03) 0.09 HBsAg at end of treatment (≥ 100 IU/mL vs < 100 IU/mL) 2.77 (1.51-5.05) <0.001 3.24 (1.75-6.01) <0.001 HBsAb at end of treatment (log mIU/mL) 0.86 (0.63-1.18) 0.35 ALT at end of treatment (log U/L) 1.04 (0.70-1.53) 0.85 AST at end of treatment (log U/L) 1.02 (0.54-1.91) 0.96 HBV DNA (log IU/mL) at 1 month after discontinuation of treatment 1.21 (1.15-1.27) <0.001 ALT (log U/L) at 1 month after discontinuation of treatment 2.19 (1.60-3.01) <0.001 HBsAg (log IU/mL) at 1 month after discontinuation of treatment 1.21 (1.08-1.35) <0.001

停止治療之後1個月時的HBV DNA、HBsAg及ALT係另外變數，顯示與單變數模型中之臨床復發的顯著關聯。然而，此等共變數從多變數模型排除，因為停止治療之後1個月時的HBV DNA及ALT與治療方案高度關聯及停止治療之後1個月時的HBsAg與治療結束HBsAg高度關聯(r = 0.93，P ＜ 0.001)。僅考慮多變數模型之治療期間測定的共變數以允許識別更具預測性的印記。HBV DNA, HBsAg and ALT were additional variables at 1 month after cessation of treatment and showed a significant association with clinical relapse in a univariate model. However, these covariates were excluded from the multivariate model because HBV DNA and ALT at 1 month after treatment discontinuation were highly associated with treatment regimen and HBsAg at 1 month after treatment discontinuation was highly associated with end-of-treatment HBsAg (r = 0.93 , P < 0.001). Only covariates determined during treatment of the multivariate model were considered to allow identification of more predictive signatures.

在110名臨床復發者中，與替諾福韋治療相比，停止恩替卡韋治療後，臨床復發之初發係平均晚100天。與低組相比，治療結束(EOT) HBsAg高組達成臨床復發的時間係平均晚60天。此可能係由於12名具有低EOT HbsAg量的患者中的7名在替諾福韋組中(與恩替卡韋組中的5名相比)。Among 110 clinical relapsers, the onset of clinical relapse was an average of 100 days later after cessation of entecavir treatment compared with tenofovir treatment. Compared with the low group, the end of treatment (EOT) HBsAg high group reached clinical relapse on average 60 days later. This may be due to the fact that 7 of 12 patients with low EOT HbsAg levels were in the tenofovir group (compared to 5 in the entecavir group).

病毒學復發 ：多變數Cox比例風險回歸分析顯示，老年(HR，1.02，95% CI，1.00–1.03；P =0.03)、NA療法開始時的先前HBeAg陰性(與在治療期間獲得HBeAg陰性相比) (HR，2.20；95% CI，1.43-3.40；P ＜ 0.001)、替諾福韋治療(與恩替卡韋治療相比) (HR，2.97；95% CI，2.10–4.20；P ＜ 0.001)及治療結束時的高HBsAg (HR，2.37；95% CI，1.51-3.74；P ＜ 0.001)增加病毒學復發的風險且因此與病毒學復發負面關聯(表2b)。 表2b. 用於病毒學復發之Cox比例風險回歸分析 共變數 單變數分析 多變數分析 HR (95% CI) P值 HR (95% CI) P值 年齡(歲) 1.01 (1.00-1.03) 0.05 1.02 (1.00-1.03) 0.03 性別(男性vs女性) 1.53 (1.05-2.23) 0.03 先前NA療法(是vs否) 1.64 (1.19-2.27) 0.003 基線HBeAg狀態(先前陰性vs治療期間) 2.02 (1.37-2.98) ＜0.001 2.2 (1.4-3.4) 0.0003 治療方案 替諾福韋vs恩替卡韋 2.49 (1.77-3.49) ＜0.001 2.97 (2.1-4.2) ＜1e-5 其他vs恩替卡韋 1.57 (0.88-2.81) 0.13 1.6 (1.6-0.9) 0.11 長度NA療法(年數) 0.99 (0.91-1.07) 0.79 治療中病毒抑制 不一致vs一致 0.94 (0.63-1.41) 0.77 無vs一致 1.17 (0.69-2.00) 0.56 治療結束時的HBV DNA (偵測到vs未偵測到) 1.08 (0.79-1.47) 0.64 治療結束時的HBsAg (≥ 100 IU/mL vs ＜ 100 IU/mL) 1.64 (1.08-2.49) 0.02 2.37 (1.51-3.74) 0.0002 治療結束時的HBsAb (log mIU/mL) 0.92 (0.73-1.16) 0.49 治療結束時的ALT (log U/L) 1.09 (0.81-1.48) 0.57 治療結束時的AST (log U/L) 1.03 (0.62-1.70) 0.93 停止治療之後1個月時的HBV DNA (log IU/mL) 1.21 (1.16-1.26) ＜0.001 停止治療之後1個月時的ALT (log U/L) 1.55 (1.23-1.97) ＜0.001 停止治療之後1個月時的HBsAg (log IU/mL) 1.08 (1.01-1.16) 0.03 Virological relapse : Multivariable Cox proportional hazards regression analysis showed that older age (HR, 1.02, 95% CI, 1.00–1.03; P = 0.03), prior HBeAg negativity at the start of NA therapy (compared with acquired HBeAg negativity during treatment) ) (HR, 2.20; 95% CI, 1.43-3.40; P < 0.001), tenofovir treatment (vs. entecavir treatment) (HR, 2.97; 95% CI, 2.10–4.20; P < 0.001), and treatment High HBsAg at the end (HR, 2.37; 95% CI, 1.51-3.74; P<0.001) increased the risk of virological relapse and was therefore negatively associated with virological relapse (Table 2b). Table 2b. Cox proportional hazards regression analysis for virological recurrence covariate Univariate Analysis multivariate analysis HR (95% CI) P value HR (95% CI) P value age) 1.01 (1.00-1.03) 0.05 1.02 (1.00-1.03) 0.03 Gender (male vs female) 1.53 (1.05-2.23) 0.03 Prior NA therapy (yes vs no) 1.64 (1.19-2.27) 0.003 Baseline HBeAg status (previously negative vs during treatment) 2.02 (1.37-2.98) <0.001 2.2 (1.4-3.4) 0.0003 treatment plan Tenofovir vs Entecavir 2.49 (1.77-3.49) <0.001 2.97 (2.1-4.2) <1e-5 Other vs Entecavir 1.57 (0.88-2.81) 0.13 1.6 (1.6-0.9) 0.11 Length of NA therapy (years) 0.99 (0.91-1.07) 0.79 Viral suppression during therapy inconsistent vs consistent 0.94 (0.63-1.41) 0.77 None vs Consistent 1.17 (0.69-2.00) 0.56 HBV DNA at the end of treatment (detected vs not detected) 1.08 (0.79-1.47) 0.64 HBsAg at end of treatment (≥ 100 IU/mL vs < 100 IU/mL) 1.64 (1.08-2.49) 0.02 2.37 (1.51-3.74) 0.0002 HBsAb at end of treatment (log mIU/mL) 0.92 (0.73-1.16) 0.49 ALT at end of treatment (log U/L) 1.09 (0.81-1.48) 0.57 AST at end of treatment (log U/L) 1.03 (0.62-1.70) 0.93 HBV DNA (log IU/mL) at 1 month after discontinuation of treatment 1.21 (1.16-1.26) <0.001 ALT (log U/L) at 1 month after discontinuation of treatment 1.55 (1.23-1.97) <0.001 HBsAg (log IU/mL) at 1 month after discontinuation of treatment 1.08 (1.01-1.16) 0.03

治療停止後1個月時的HBV DNA、HBsAg及ALT再次從多變數模型排除，因為與治療方案及治療結束HBsAg的強關聯。最後，基線HBeAg與年齡(P ＜ 0.001)及性別(P = 0.03)相關聯，且因此亦從多變數模型排除。在一個相對不平衡的定群中，性別及年齡之效應為中等，且HBeAg狀態更能反映患者之慢性期。HBV DNA, HBsAg, and ALT at 1 month after treatment discontinuation were again excluded from the multivariate model because of the strong association with treatment regimen and end-of-treatment HBsAg. Finally, baseline HBeAg was associated with age (P < 0.001) and sex (P = 0.03) and was therefore also excluded from the multivariate model. In a relatively unbalanced cohort, the effects of gender and age were moderate, and HBeAg status more closely reflected the chronic phase of patients.

持續臨床反應：邏輯回歸顯示NA療法開始時的先前HBeAg陰性(OR，0.25；95% CI，0.06–0.99；P = 0.05)、治療結束時的高HbsAg (OR，0.16；95% CI，0.04–0.55；P = 0.0005)及停止治療後1個月時較高的HBV DNA (OR，0.54；95% CI，0.28–0.78；P = 0.01)與持續臨床反應的負面關聯(表2c)。 表2c. 持續臨床反應之邏輯回歸分析 共變數 單變數分析 多變數分析 OR (95% CI) P值 OR (95% CI) P值 年齡(歲) 0.98 (0.94-1.01) 0.21 性別(男性vs女性) 0.43 (0.17-1.10) 0.07 先前NA療法(是vs否) 0.64 (0.22-1.63) 0.37    基線HBeAg狀態(先前陰性vs治療期間) 0.34 (0.14-0.87) 0.02 0.25 (0.06-0.99) 0.05 治療方案 替諾福韋vs恩替卡韋 0.79 (0.29-2.03) 0.64 其他vs恩替卡韋 1.01 (0.15-4.20) 0.99 長度NA療法(年數) 1.01 (0.79-1.24) 0.93 治療中病毒抑制 不一致vs一致 0.81 (0.30-2.40) 0.68 無vs一致 0.21 (0.01-1.36) 0.16 治療結束時的HBV DNA (偵測到相對未偵測到) 0.69 (0.28-1.65) 0.41 治療結束時的HBsAg (≥ 100 IU/mL vs＜ 100 IU/mL) 0.23 (0.09-0.57) 0.001 0.16 (0.04-0.55)  0.005 治療結束時的HBsAb (log mIU/mL) 1.32 (0.78-2.04) 0.22 治療結束時的ALT (log U/L) 1.40 (0.55-3.59) 0.48 治療結束時的AST (log U/L) 1.34 (0.29-5.79) 0.7 停止治療之後1個月時的HBV DNA (log IU/mL) 0.53 (0.27-0.77) 0.01 0.54 (0.28-0.78) 0.01 停止治療之後1個月時的ALT (log U/L) 0.59 (0.25-1.21) 0.2 停止治療之後1個月時的HBsAg (log IU/mL) 0.72 (0.59-0.86) ＜0.001 Sustained clinical response: Logistic regression showed negative prior HBeAg at initiation of NA therapy (OR, 0.25; 95% CI, 0.06–0.99; P = 0.05), high HbsAg at end of treatment (OR, 0.16; 95% CI, 0.04– 0.55; P = 0.0005) and higher HBV DNA at 1 month after discontinuation of treatment (OR, 0.54; 95% CI, 0.28–0.78; P = 0.01) was negatively associated with sustained clinical response (Table 2c). Table 2c. Logistic Regression Analysis of Sustained Clinical Response covariate Univariate Analysis multivariate analysis OR (95% CI) P value OR (95% CI) P value age) 0.98 (0.94-1.01) 0.21 Gender (male vs female) 0.43 (0.17-1.10) 0.07 Prior NA therapy (yes vs no) 0.64 (0.22-1.63) 0.37 Baseline HBeAg status (previously negative vs during treatment) 0.34 (0.14-0.87) 0.02 0.25 (0.06-0.99) 0.05 treatment plan Tenofovir vs Entecavir 0.79 (0.29-2.03) 0.64 Other vs Entecavir 1.01 (0.15-4.20) 0.99 Length of NA therapy (years) 1.01 (0.79-1.24) 0.93 Viral suppression during therapy inconsistent vs consistent 0.81 (0.30-2.40) 0.68 None vs Consistent 0.21 (0.01-1.36) 0.16 HBV DNA at end of treatment (detected versus undetected) 0.69 (0.28-1.65) 0.41 HBsAg at end of treatment (≥ 100 IU/mL vs < 100 IU/mL) 0.23 (0.09-0.57) 0.001 0.16 (0.04-0.55) 0.005 HBsAb at end of treatment (log mIU/mL) 1.32 (0.78-2.04) 0.22 ALT at end of treatment (log U/L) 1.40 (0.55-3.59) 0.48 AST at end of treatment (log U/L) 1.34 (0.29-5.79) 0.7 HBV DNA (log IU/mL) at 1 month after discontinuation of treatment 0.53 (0.27-0.77) 0.01 0.54 (0.28-0.78) 0.01 ALT (log U/L) at 1 month after discontinuation of treatment 0.59 (0.25-1.21) 0.2 HBsAg (log IU/mL) at 1 month after discontinuation of treatment 0.72 (0.59-0.86) <0.001

基線HBeAg與年齡( P ＜ 0.001 )和性別( P = 0.03 )有關，且因此不包括在包括HLA標記的模型中。反映患者慢性期的HBeAg狀態，此共變數不包括在多變數模型中。停止治療後1個月的HBV DNA再次被排除在多變數模型之外，因為僅考慮到治療中共變數以獲得更具預測性的印記。 Baseline HBeAg was associated with age (P<0.001) and sex (P=0.03) and was therefore not included in the model including HLA markers. Reflecting the HBeAg status of patients in the chronic phase, this covariate was not included in the multivariate model. HBV DNA 1 month after discontinuation of treatment was again excluded from the multivariate model because only treatment covariates were considered for a more predictive signature.

HLA對偶基因、同合性及HED分佈：此定群中不同HLA對偶基因的整體頻率及分佈概述於圖2A (兩位解析度)和圖2B (四位解析度)。類似地，六個基因座之每一者的每個對偶基因的同合性之整體頻率和分佈概述於圖3A（兩位解析度）和圖3B（四位解析度）。HLA-dual genes, homozygosity, and HED distribution: The overall frequency and distribution of the different HLA-dual genes in this cohort is summarized in Figure 2A (two-digit resolution) and Figure 2B (four-digit resolution). Similarly, the overall frequency and distribution of homozygosity for each dual gene for each of the six loci are summarized in Figure 3A (two-digit resolution) and Figure 3B (four-digit resolution).

對於各患者，在各基因座及各HLA區域(I類及II類)內，可以導出每個基因座的HED分數。此定群內的每位基因座的HED分數的整體分佈概述於圖4，顯示HLA-DQB1及HLA-DRB1區域的相對較高HLA多樣性。對於各HLA區域及各分析(病毒學復發之初發、臨床復發之初發、持續臨床反應)，定義最佳截止值。所有截止值概述於表3中，將定群分成高HLA演化多樣性/低HLA演化多樣性。表3顯示所獲得的HED臨限值及所導出的相應分類變數的綜述。＞臨限值的非缺失HED分數被分配為高，否則為低。在進行的三項分析(與病毒學復發之初發、臨床復發之初發及持續臨床反應相關)，對各HLA基因導出一個截止值。 表3 類別 分析 / 模型 HLA 基因 變數 臨限值 I類 CR HLA-A HED_HLA_A_CAT_CR 3.88 I類 CR HLA-B HED_HLA_B_CAT_CR 9.38 I類 CR HLA-C HED_HLA_C_CAT_CR 0.00 I類 CR MEAN_MHCI HED_MEANI_CAT_CR 6.35 I類 VR HLA-A HED_HLA_A_CAT_VR 3.88 I類 VR HLA-B HED_HLA_B_CAT_VR 9.37 I類 VR HLA-C HED_HLA_C_CAT_VR 0.00 I類 VR MEAN_MHCI HED_MEANI_CAT_VR 8.69 I類 SCR HLA-A HED_HLA_A_CAT_SCR 4.85 I類 SCR HLA-B HED_HLA_B_CAT_SCR 9.38 I類 SCR HLA-C HED_HLA_C_CAT_SCR 7.37 I類 SCR MEAN_MHCI HED_MEANI_CAT_SCR 7.61 II類 CR HLA-DPB1 HED_HLA_P_CAT_CR 4.15 II類 CR HLA-DQB1 HED_HLA_Q_CAT_CR 11.72 II類 CR HLA-DRB1 HED_HLA_R_CAT_CR 12.68 II類 CR MEAN_MHCII HED_MEANII_CAT_CR 7.67 II類 VR HLA-DPB1 HED_HLA_P_CAT_VR 2.21 II類 VR HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 II類 VR HLA-DRB1 HED_HLA_R_CAT_VR 12.68 II類 VR MEAN_MHCII HED_MEANII_CAT_VR 7.55 II類 SCR HLA-DPB1 HED_HLA_P_CAT_SCR 2.43 II類 SCR HLA-DQB1 HED_HLA_Q_CAT_SCR 11.72 II類 SCR HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 II類 SCR MEAN_MHCII HED_MEANII_CAT_SCR 8.21 For each patient, within each locus and each HLA region (class I and class II), a HED score for each locus can be derived. The overall distribution of HED scores per locus within this cohort is summarized in Figure 4, showing relatively high HLA diversity in the HLA-DQB1 and HLA-DRB1 regions. For each HLA region and each analysis (initial onset of virological relapse, onset of clinical relapse, sustained clinical response), optimal cutoff values were defined. All cutoffs are summarized in Table 3, dividing the cohort into high HLA evolutionary diversity/low HLA evolutionary diversity. Table 3 shows a summary of the HED thresholds obtained and the corresponding categorical variables derived. Non-missing HED scores >threshold value were assigned high, otherwise low. In the three analyses performed (associated with onset of virological relapse, onset of clinical relapse, and sustained clinical response), a cutoff value was derived for each HLA gene. table 3 category Analysis / Model HLA gene variable Threshold value Class I CR HLA-A HED_HLA_A_CAT_CR 3.88 Class I CR HLA-B HED_HLA_B_CAT_CR 9.38 Class I CR HLA-C HED_HLA_C_CAT_CR 0.00 Class I CR MEAN_MHCI HED_MEANI_CAT_CR 6.35 Class I VR HLA-A HED_HLA_A_CAT_VR 3.88 Class I VR HLA-B HED_HLA_B_CAT_VR 9.37 Class I VR HLA-C HED_HLA_C_CAT_VR 0.00 Class I VR MEAN_MHCI HED_MEANI_CAT_VR 8.69 Class I SCR HLA-A HED_HLA_A_CAT_SCR 4.85 Class I SCR HLA-B HED_HLA_B_CAT_SCR 9.38 Class I SCR HLA-C HED_HLA_C_CAT_SCR 7.37 Class I SCR MEAN_MHCI HED_MEANI_CAT_SCR 7.61 Class II CR HLA-DPB1 HED_HLA_P_CAT_CR 4.15 Class II CR HLA-DQB1 HED_HLA_Q_CAT_CR 11.72 Class II CR HLA-DRB1 HED_HLA_R_CAT_CR 12.68 Class II CR MEAN_MHCII HED_MEANII_CAT_CR 7.67 Class II VR HLA-DPB1 HED_HLA_P_CAT_VR 2.21 Class II VR HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 Class II VR HLA-DRB1 HED_HLA_R_CAT_VR 12.68 Class II VR MEAN_MHCII HED_MEANII_CAT_VR 7.55 Class II SCR HLA-DPB1 HED_HLA_P_CAT_SCR 2.43 Class II SCR HLA-DQB1 HED_HLA_Q_CAT_SCR 11.72 Class II SCR HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 Class II SCR MEAN_MHCII HED_MEANII_CAT_SCR 8.21

HLA對偶基因與復發之初發及持續臨床反應之關聯：有趣的是，在HLA-B及HLA-C基因座中，HLA I類區域中之若干HLA對偶基因顯示與病毒學復發之初發或持續臨床反應顯著關聯(更多B*51對偶基因、更少C*07:02對偶基因及更多C*15:02對偶基因可保護性抵抗病毒學復發) (表4，圖6A至D)。Association of HLA-dual genes with onset of relapse and sustained clinical response: Interestingly, at the HLA-B and HLA-C loci, several HLA-dual genes in HLA class I regions were shown to be associated with onset or onset of virological relapse. Sustained clinical response significantly associated (more B*51 counterparts, less C*07:02 counterparts, and more C*15:02 counterparts for protection against virological relapse) (Table 4, Figures 6A to D) .

HLA對偶基因(兩位解析度)與病毒學復發之初發及/或持續臨床反應顯著關聯。如圖6A至6C中所示，B*51 (A)、C*07 (B)及C*15 (C)對偶基因之卡普蘭-邁爾曲線與病毒學復發之初發相關聯，及條形圖代表持續臨床反應者體內B*51對偶基因(A) (圖6A)及C*15對偶基因(C) (圖6C)的存在或不存在之分佈。HLA dual genes (two-digit resolution) were significantly associated with initial and/or persistent clinical response to virological relapse. As shown in Figures 6A-6C, Kaplan-Meier curves for the B*51 (A), C*07 (B), and C*15 (C) paired genes were associated with the onset of virological relapse, and bar The graphs represent the distribution of the presence or absence of the B*51 counterpart (A) (FIG. 6A) and the C*15 counterpart (C) (FIG. 6C) in sustained clinical responders.

如圖6D中所示，HLA-C區域中之單核苷酸多型性(SNP)顯示相似顯著性水平(p值＜1e-6)，而測試與病毒學或臨床復發之初發之關聯作為候選方法。p值圖相對於來自臨床復發之初發(頂部小圖)或病毒復發之初發(第2小圖)之GWAS關聯分析之基因組位置。各點對應於SNP之p值。標記指示對應於所獲得的最低p值之SNP之RS識別碼。中間小圖顯示使用r2作為度量的SNP對之間的連鎖不平衡。底部小圖提供包含在跨越基因的基因組區域(+/- 7000 bp)中之該等基因的綜述。基因跨越該區域以及axiom晶片(底部軌跡)上的SNP及染色體上的位置之覆蓋。於基因座之基因分型後，小圖右側的線及標記顯示於HLA對偶基因之測試之p值。標記對應於具有所獲得的最低p值之5個對偶基因。As shown in Figure 6D, single nucleotide polytypes (SNPs) in the HLA-C region showed similar levels of significance (p-value < le-6) while testing for association with onset of virological or clinical relapse as a candidate method. The p-values are plotted against genomic positions from GWAS association analyses of clinical relapse (top panel) or viral relapse (2nd panel). Each point corresponds to the p-value of the SNP. The marker indicates the RS identifier of the SNP corresponding to the lowest p-value obtained. The middle panel shows linkage disequilibrium between pairs of SNPs using r2 as a measure. The bottom panel provides a summary of the genes contained in the genomic region (+/- 7000 bp) spanning the genes. The gene spans this region and coverage of SNPs and chromosomal locations on the axiom wafer (bottom trace). After genotyping of the loci, the lines and markers on the right side of the panels show the p-values of the tests for the HLA pair. Markers correspond to the 5 dual genes with the lowest p-value obtained.

在HLA-C蛋白與自然殺手細胞上之KIR及LILR配體相互作用時，已探查白血球受體複合物(LRC)區域上之SNP (圖6，圖E)，顯示LILRB4、LILRA4及LILRB5基因及KIR3DL1、KIR2DL4、KIR2DL2及KIR2DL3基因中的顯著關聯(p值＜0.05) (表4c，圖6E)。圖6E表示包括KIR配體的白血球受體複合物中的SNP (LRC區域定義於(GRCh37.p13)：CHR 19 54528888-55595686中)與病毒學及臨床復發之初發之間的關聯。p值圖係相對於來自臨床復發之初發(頂部小圖)或病毒復發之初發(第2小圖)之GWAS關聯分析之基因組位置。各點對應於SNP之p值。標記指示對應於10個最低p值之SNP之RS識別碼。中間小圖顯示使用r2作為度量的SNP對之間的連鎖不平衡。底部小圖提供包含在基因組區域19:54528888-55595686中之基因的綜述。該等基因跨越該區域以及axiom晶片(底部軌跡)上的SNPs及染色體上的位置之涵蓋範圍。SNPs on the leukocyte receptor complex (LRC) region have been probed when HLA-C protein interacts with KIR and LILR ligands on natural killer cells (Fig. 6, panel E), showing that LILRB4, LILRA4 and LILRB5 genes and Significant associations (p-value < 0.05) in the KIR3DL1, KIR2DL4, KIR2DL2 and KIR2DL3 genes (Table 4c, Figure 6E). Figure 6E shows the association between SNPs in leukocyte receptor complexes including KIR ligands (LRC region is defined in (GRCh37.p13): CHR 19 54528888-55595686) and virological and clinical relapse onset. The p-values are plotted relative to genomic position from GWAS association analysis of clinical relapse (top panel) or viral relapse (2nd panel). Each point corresponds to the p-value of the SNP. Labels indicate the RS identifiers of the SNPs corresponding to the 10 lowest p-values. The middle panel shows linkage disequilibrium between pairs of SNPs using r2 as a measure. The bottom panel provides an overview of the genes contained in the genomic region 19:54528888-55595686. The genes span this region and the coverage of SNPs and chromosomal locations on the axiom wafer (bottom trace).

表4a展現在多次測試校正(錯誤發現率＜10%)後與病毒學復發之初發或持續臨床反應顯著關聯的HLA對偶基因的綜述。對於與復發之初發的關聯，將治療中最後一次就診及最後治療方案時的HBsAg量視為主要效應；對於測試與持續臨床反應的關聯，將治療中最後一次就診時的HBsAg量視為主要效應。表4b展現HLA-C區域中之SNPs與復發之初發顯著(未調整p值＜0.05)關聯的綜述(將治療方案視為主要效應)。表4c展現LRC區域中之SNPs與復發之初發顯著(未調整p值＜0.05)關聯的綜述(將治療方案視為主要效應)。Table 4a presents a summary of HLA counterpart genes significantly associated with initial or sustained clinical response to virological relapse after correction for multiple testing (false discovery rate <10%). For the association with onset of relapse, the HBsAg level at the last treatment visit and last regimen was considered as the main effect; for the test for the association with sustained clinical response, the HBsAg level at the last treatment visit was considered as the main effect effect. Table 4b presents a summary of the significant (unadjusted p-value < 0.05) association of SNPs in the HLA-C region with onset of recurrence (treatment regimen was considered the main effect). Table 4c presents a summary of the significant (unadjusted p-value < 0.05) association of SNPs in the LRC region with onset of recurrence (treatment regimen was considered as the main effect).

在此定群中，未觀測到HLA對偶基因與臨床復發之初發之顯著關聯，且在多次測試校正之後，未觀測到HLA同合性(homozygosity)與復發之初發或持續臨床反應之間的顯著關聯(圖5)。 表4a 對偶基因 基因座 位 MAF SINGLE_F 分析 術語 估算值 p 值 FDR 保護性 B*51 HLA-B 2位 0.10 錯誤 VR ADD -0.91 0.00 0.06 更多 B*51 HLA-B 2位 0.10 錯誤 SCR ADD 1.91 0.00 0.09 更多 C*07 HLA-C 2位 0.40 錯誤 VR ADD 0.70 0.00 0.00 更少 C*07:02 HLA-C 4位 0.38 錯誤 VR ADD 0.65 0.00 0.00 更少 C*15 HLA-C 2位 0.10 錯誤 VR ADD -0.87 0.00 0.06 更多 C*15 HLA-C 2位 0.10 錯誤 SCR ADD 1.83 0.00 0.09 更多 C*15:02 HLA-C 4位 0.10 錯誤 VR ADD -0.87 0.00 0.06 更多 C*15:02 HLA-C 4位 0.10 錯誤 SCR ADD 1.83 0.00 0.09 更多 表4b SNP RSID 基因 CHR POS 估算值 P值 反應 起源 A1 A2 MAF 風險 對偶 基因 保護性對偶基因 AX-11389327 rs2394952 HLA-C 6 31230882 0.728044 6.66390146064622e-7 病毒性復發 MHC Candidate Top G A 0.2225 G A AX-11435438 rs3130542 HLA-C 6 31232111 0.728044 6.66390146064622e-7 病毒性復發 MHC Candidate Top A G 0.2225 A G AX-11425415 rs2894202 HLA-C 6 31233270 0.728044 6.66390146064622e-7 病毒性復發 MHC Candidate Top T G 0.2225 T G AX-15354727 rs9264523 HLA-C 6 31233758 0.728044 6.66390146064622e-7 病毒性復發 MHC Candidate Top T A 0.2225 T A AX-11110708 rs1049281 HLA-C 6 31236567 0.728044 6.66390146064622e-7 病毒性復發 MHC Candidate Top T C 0.2225 T C AX-35731691 rs9264643 HLA-C 6 31238492 0.728044 6.66390146064622e-7 病毒性復發 MHC Candidate Top C A 0.2225 C A AX-83069277 rs1130838 HLA-C 6 31237124 0.774919 7.26418708851817e-7 病毒性復發 MHC Candidate Top T C 0.2139 T C AX-11389316 rs2394888 HLA-C 6 31202246 0.706182 1.02E-06 病毒性復發 MHC Candidate Top A G 0.217 A G AX-83089411 HLA-C 6 31237768 0.710822 1.16E-06 病毒性復發 MHC Candidate Top AGC T 0.2225 AGC T AX-83033597 rs2308622 HLA-C 6 31238029 0.815332 1.7E-06 病毒性復發 MHC Candidate Top T C 0.2056 T C AX-11676212 rs9264416 HLA-C 6 31230042 0.676271 4.21E-06 病毒性復發 MHC Candidate Top G A 0.2115 G A AX-41951051 rs2001181 HLA-C 6 31236998 0.676271 4.21E-06 病毒性復發 MHC Candidate Top C T 0.2115 C T AX-11435692 rs3132499 HLA-C 6 31207920 0.669243 5.54E-06 病毒性復發 MHC Candidate Top C T 0.2088 C T AX-11435436 rs3130532 HLA-C 6 31208453 0.669243 5.54E-06 病毒性復發 MHC Candidate Top A G 0.2088 A G AX-15354622 rs3130941 HLA-C 6 31197514 0.662868 7.75E-06 病毒性復發 MHC Candidate Top C G 0.2072 C G AX-11435434 rs3130528 HLA-C 6 31199460 0.598808 1.66E-05 病毒性復發 MHC Candidate Top T C 0.2115 T C AX-11435919 rs3134782 HLA-C 6 31197633 0.573613 1.68E-05 病毒性復發 MHC Candidate Top G A 0.221 G A AX-11435916 rs3134769 HLA-C 6 31205754 0.5054 7.72E-05 病毒性復發 MHC Candidate Top T C 0.3324 T C AX-11435432 rs3130521 HLA-C 6 31196376 0.510141 8.18E-05 病毒性復發 MHC Candidate Top T C 0.3287 T C AX-82884445 rs3130695 HLA-C 6 31211050 0.470284 0.000258 病毒性復發 MHC Candidate Top A G 0.3242 A G AX-15354633 rs3130685 HLA-C 6 31206206 -0.42529 0.00026 病毒性復發 MHC Candidate Top T C 0.4973 C T AX-15354698 rs2524119 HLA-C 6 31229404 0.380815 0.000772 病毒性復發 MHC Candidate Top T C 0.2869 T C AX-11435433 rs3130527 HLA-C 6 31198987 0.389965 0.003003 病毒性復發 MHC Candidate Top T C 0.2967 T C AX-11425411 rs2894186 HLA-C 6 31206868 -0.31881 0.008845 病毒性復發 MHC Candidate Top C G 0.4011 G C AX-50495706 rs3130439 HLA-C 6 31221023 -0.23878 0.015167 病毒性復發 MHC Candidate Top A G 0.5 G A AX-11433206 rs3095254 HLA-C 6 31221668 0.27173 0.01963 病毒性復發 MHC Candidate Top C G 0.3591 C G AX-11676201 rs9264189 HLA-C 6 31220163 0.249459 0.02553 病毒性復發 MHC Candidate Top A C 0.4282 A C AX-11389323 rs2394943 HLA-C 6 31220388 0.247638 0.025585 病毒性復發 MHC Candidate Top T C 0.4313 T C AX-11685437 rs9394047 HLA-C 6 31236250 -0.27896 0.031231 病毒性復發 MHC Candidate Top C A 0.2652 A C AX-11435538 rs3130948 HLA-C 6 31193523 -0.21961 0.032006 病毒性復發 MHC Candidate Top T C 0.3785 C T AX-15354704 rs9368666 HLA-C 6 31229644 -0.24909 0.045811 病毒性復發 MHC Candidate Top G A 0.275 A G AX-11435536 rs3130942 HLA-C 6 31197293 -0.25822 0.047561 病毒性復發 MHC Candidate Top T C 0.3956 C T AX-11435471 rs3130688 HLA-C 6 31210216 0.251956 0.049806 病毒性復發 MHC Candidate Top C T 0.4203 C T AX-11417845 rs3130536 HLA-C 6 31210532 0.251956 0.049806 病毒性復發 MHC Candidate Top A G 0.4203 A G AX-11435914 rs3134750 HLA-C 6 31218087 0.251956 0.049806 病毒性復發 MHC Candidate Top A G 0.4203 A G AX-11490436 rs4084090 HLA-C 6 31218835 -0.50926 0.029462 臨床復發 MHC Candidate Bottom G A 0.1181 A G AX-35731063 rs9264127 HLA-C 6 31211592 -0.5527 0.030238 臨床復發 MHC Candidate Bottom G C 0.1023 C G AX-11676190 rs9264039 HLA-C 6 31196591 -0.47866 0.040352 臨床復發 MHC Candidate Bottom A G 0.1154 G A AX-11485919 rs3868078 HLA-C 6 31199164 -0.47866 0.040352 臨床復發 MHC Candidate Bottom T C 0.1154 C T 表4c SNP RSID 基因 CHR POS 估算值 P值 反應 MAF 風險 對偶 基因 保 護 性 對 偶 基 因 AX-40474401 rs10426302 --- 19 55211547 0.451712561 0.000240387 病毒性復發 0.3654 G A AX-32791043 rs59537494 MBOAT7 19 54688378 0.476837708 0.000678068 病毒性復發 0.2198 G C AX-32793765 rs28366008 LILRB4 19 55174498 -0.513992692 0.000925382 病毒性復發 0.1519 T C AX-32791067 rs36625 MBOAT7 19 54692523 0.355084386 0.001107075 病毒性復發 0.4011 A G AX-11562447 rs635608 TSEN34 19 54696488 0.344914709 0.001176932 病毒性復發 0.4643 C T AX-40473181 rs7595 TSEN34 19 54697079 0.344914709 0.001176932 病毒性復發 0.4643 T C AX-83323675 rs731170 LILRB4 19 55176262 -0.468562637 0.001187372 病毒性復發 0.239 G A AX-13455041 rs28513 --- 19 54699386 0.366160334 0.001868607 病毒性復發 0.4973 C A AX-32795451 rs12459334 EPS8L1 19 55588726 0.533351627 0.003247705 病毒性復發 0.1016 C T AX-51295385 rs11666535 --- 19 55217660 0.410213441 0.003485518 病毒性復發 0.2639 G T AX-11527755 rs4806807 --- 19 55207900 0.359721702 0.004576148 病毒性復發 0.3407 G T AX-40474407 rs11084367 --- 19 55213281 0.323708459 0.005596541 病毒性復發 0.4973 G A AX-40473175 rs39714 MBOAT7 19 54693682 0.295723304 0.005852794 病毒性復發 0.4536 C G AX-32795469 rs1654474 EPS8L1 19 55590594 0.496196364 0.006516564 病毒性復發 0.1016 T C AX-11207928 rs12462907 GP6 19 55529100 0.24216561 0.006911051 病毒性復發 0.306 T C AX-11643598 rs775893 NLRP2 19 55486167 -0.290614208 0.011613591 病毒性復發 0.3352 C G AX-12388453 rs10416527 --- 19 55215632 0.287752966 0.012488897 病毒性復發 0.4835 G A AX-11505772 rs4441391 --- 19 55216681 0.287752966 0.012488897 病毒性復發 0.4835 G A AX-40473161 rs40167 MBOAT7 19 54682975 0.268925659 0.013809827 病毒性復發 0.4836 G A AX-32792529 rs11084339 TTYH1 19 54948086 -0.444904956 0.014154957 病毒性復發 0.1566 G A AX-40474775 rs775875 NLRP7 19 55446522 0.262662903 0.015424157 病毒性復發 0.478 T A AX-40474665 rs2304225 FCAR 19 55385962 0.374671188 0.016022686 病毒性復發 0.1806 G C AX-13454965 rs4077076 VSTM1 19 54558412 -0.286459718 0.018143745 病毒性復發 0.2374 G A AX-40472901 rs4442924 VSTM1 19 54554942 0.356012339 0.018388072 病毒性復發 0.1951 C A AX-11527741 rs4806527 KIR3DL1 19 55228948 -0.254093802 0.022274657 病毒性復發 0.4836 G A AX-83135617 rs12608979 RDH13 19 55568084 0.377246744 0.022286121 病毒性復發 0.1519 T C AX-11479003 rs3765013 COSV52557220 NCR1 19 55420801 -0.242495817 0.022506041 病毒性復發 0.467 C A AX-40474663 rs12462181 --- 19 55385435 0.288971856 0.022787314 病毒性復發 0.3022 C T AX-13455616 rs2075731 COSV52550169 KIR3DL3 19 55237616 0.258917784 0.02605448 病毒性復發 0.4062 C T AX-32795291 rs12608988 RDH13 19 55567979 0.366644765 0.026168426 病毒性復發 0.1511 A G AX-94351577 rs190480734 KIR2DL4 19 55307719 0.1850665 0.026403665 病毒性復發 0.3825 A G AX-40475037 rs1654452 RDH13 19 55572284 0.322538925 0.026843638 病毒性復發 0.1841 A G AX-32794129 rs11879415 KIR2DL4 19 55276380 -0.260151598 0.027476482 病毒性復發 0.3861 C T AX-40473143 rs653560 TMC4 19 54677103 -0.246315381 0.028071892 病毒性復發 0.4725 C G AX-40475023 rs11084387 RDH13 19 55565352 0.359882921 0.028445048 病毒性復發 0.1538 A G AX-11166815 rs11672111 RDH13 19 55565634 0.359882921 0.028445048 病毒性復發 0.1538 C G AX-40475027 rs10424969 RDH13 19 55566512 0.359882921 0.028445048 病毒性復發 0.1538 G T AX-32792987 rs77389424 LAIR2 19 55028970 0.348600312 0.030102735 病毒性復發 0.1243 C T AX-11477710 rs3745902 CM1111041 KIR3DL2 19 55378008 0.275803142 0.030573053 病毒性復發 0.2995 T C AX-11166876 rs11672983 --- 19 55383051 0.275803142 0.030573053 病毒性復發 0.2995 A G AX-40473637 rs17836364 LILRA4 19 54847587 -0.310174266 0.031362692 病毒性復發 0.2238 G A AX-32794537 rs34549987 NCR1 19 55416954 -0.226798441 0.032477939 病毒性復發 0.5 T C AX-40473405 rs11668526 RPS9 19 54749060 -0.320096266 0.032759469 病毒性復發 0.2363 C T AX-11166583 rs11667105 NLRP2 19 55509865 0.215814943 0.03295294 病毒性復發 0.2857 A G AX-40474339 rs1749282 --- 19 55194821 -0.238413105 0.034679844 病毒性復發 0.3654 A G AX-11280328 rs1654660 --- 19 55195187 -0.238413105 0.034679844 病毒性復發 0.3654 G A AX-13455605 rs73618328 KIR3DL1 19 55228122 -0.237775016 0.035164827 病毒性復發 0.4808 T C AX-32794029 rs270785 KIR3DL1 19 55233850 0.315362658 0.035843002 病毒性復發 0.239 T C AX-83521570 rs76522818 LILRB5 19 54755918 0.410121214 0.037299895 病毒性復發 0.1126 G C AX-94364811 rs62131745 KIR3DL1 19 55234854 -0.228255819 0.038842978 病毒性復發 0.4973 T C AX-40473651 rs2241384 LILRA4 19 54849942 0.275552297 0.040517637 病毒性復發 0.2308 A G AX-12454687 rs1325158 KIR3DL1 19 55226402 0.238167326 0.041514617 病毒性復發 0.4093 C T AX-11112044 rs10500318 KIR2DL4 19 55320779 0.333357496 0.042556048 病毒性復發 0.1484 A G AX-11482916 rs3816051 --- 19 55385604 0.227606755 0.046660994 病毒性復發 0.3674 C T AX-32794205 rs34508934 KIR2DL4 19 55311067 0.311133039 0.047553752 病毒性復發 0.1456 A C AX-13455932 rs12460627 GP6 19 55529089 0.231413661 0.047739197 病毒性復發 0.3764 C G AX-40473767 rs11667812 TTYH1 19 54913994 0.36934225 0.006864808 臨床復發 0.3819 G C AX-13455223 rs12974194 TTYH1 19 54914134 0.36934225 0.006864808 臨床復發 0.3819 T C AX-40473637 rs17836364 LILRA4 19 54847587 -0.478999864 0.007304168 臨床復發 0.2238 G A AX-40473755 rs11669431 TTYH1 19 54903416 -0.356897282 0.010503394 臨床復發 0.4341 A C AX-11234805 rs12984962 --- 19 54769205 -0.611762362 0.01597391 臨床復發 0.1264 T C AX-32791879 rs1761462 LILRA4 19 54824667 -0.400809784 0.021889851 臨床復發 0.2747 C T AX-32794831 rs4806464 NLRP2 19 55490720 -0.436542373 0.02288708 臨床復發 0.2155 T C AX-11442739 rs34190750 --- 19 55050562 0.308344304 0.022922586 臨床復發 0.3516 T C AX-32793975 rs28681595 LILRP2 19 55218126 0.353842095 0.02328333 臨床復發 0.2225 C T AX-94348052 rs12610675 TTYH1 19 54905393 0.29328675 0.024360008 臨床復發 0.4171 A G AX-32792425 rs12463051 TTYH1 19 54930952 -0.315289374 0.03099842 臨床復發 0.3956 G A AX-40474339 rs1749282 --- 19 55194821 -0.303231998 0.031723819 臨床復發 0.3654 A G AX-11280328 rs1654660 --- 19 55195187 -0.303231998 0.031723819 臨床復發 0.3654 G A AX-32795157 rs41275824 GP6 19 55543973 0.284695244 0.034010136 臨床復發 0.467 T C AX-40473651 rs2241384 LILRA4 19 54849942 0.342303097 0.037110016 臨床復發 0.2308 A G AX-11234761 rs12983338 --- 19 55210931 0.352021106 0.038636205 臨床復發 0.1566 C T AX-40474129 rs272408 LILRB1 19 55103603 0.328062285 0.041219535 臨床復發 0.3462 C T AX-40474859 rs10412569 NLRP2 19 55497855 -0.352993676 0.041637332 臨床復發 0.2335 A G AX-32794851 NLRP2 19 55493651 -0.352120385 0.045745286 臨床復發 0.228 C T AX-13455842 rs622941 NLRP7 19 55434458 -0.265313309 0.049245636 臨床復發 0.4669 C G AX-13455332 rs60690598 --- 19 55052198 0.297260211 0.049943394 臨床復發 0.2225 T C In this cohort, no significant association of HLA dual genes with onset of clinical relapse was observed, and no association of HLA homozygosity with onset of relapse or sustained clinical response was observed after correction for multiple testing There was a significant correlation between them (Figure 5). Table 4a dual gene locus bit MAF SINGLE_F analyze the term estimated value p -value FDR protective B*51 HLA-B 2 digits 0.10 mistake VR ADD -0.91 0.00 0.06 More B*51 HLA-B 2 digits 0.10 mistake SCR ADD 1.91 0.00 0.09 More C*07 HLA-C 2 digits 0.40 mistake VR ADD 0.70 0.00 0.00 less C*07:02 HLA-C 4 0.38 mistake VR ADD 0.65 0.00 0.00 less C*15 HLA-C 2 digits 0.10 mistake VR ADD -0.87 0.00 0.06 More C*15 HLA-C 2 digits 0.10 mistake SCR ADD 1.83 0.00 0.09 More C*15:02 HLA-C 4 0.10 mistake VR ADD -0.87 0.00 0.06 More C*15:02 HLA-C 4 0.10 mistake SCR ADD 1.83 0.00 0.09 More Table 4b SNP RSID Gene CHR POS estimated value P value reaction origin A1 A2 MAF risk pair gene protective pair AX-11389327 rs2394952 HLA-C 6 31230882 0.728044 6.66390146064622e-7 viral relapse MHC Candidate Top G A 0.2225 G A AX-11435438 rs3130542 HLA-C 6 31232111 0.728044 6.66390146064622e-7 viral relapse MHC Candidate Top A G 0.2225 A G AX-11425415 rs2894202 HLA-C 6 31233270 0.728044 6.66390146064622e-7 viral relapse MHC Candidate Top T G 0.2225 T G AX-15354727 rs9264523 HLA-C 6 31233758 0.728044 6.66390146064622e-7 viral relapse MHC Candidate Top T A 0.2225 T A AX-11110708 rs1049281 HLA-C 6 31236567 0.728044 6.66390146064622e-7 viral relapse MHC Candidate Top T C 0.2225 T C AX-35731691 rs9264643 HLA-C 6 31238492 0.728044 6.66390146064622e-7 viral relapse MHC Candidate Top C A 0.2225 C A AX-83069277 rs1130838 HLA-C 6 31237124 0.774919 7.26418708851817e-7 viral relapse MHC Candidate Top T C 0.2139 T C AX-11389316 rs2394888 HLA-C 6 31202246 0.706182 1.02E-06 viral relapse MHC Candidate Top A G 0.217 A G AX-83089411 HLA-C 6 31237768 0.710822 1.16E-06 viral relapse MHC Candidate Top AGC T 0.2225 AGC T AX-83033597 rs2308622 HLA-C 6 31238029 0.815332 1.7E-06 viral relapse MHC Candidate Top T C 0.2056 T C AX-11676212 rs9264416 HLA-C 6 31230042 0.676271 4.21E-06 viral relapse MHC Candidate Top G A 0.2115 G A AX-41951051 rs2001181 HLA-C 6 31236998 0.676271 4.21E-06 viral relapse MHC Candidate Top C T 0.2115 C T AX-11435692 rs3132499 HLA-C 6 31207920 0.669243 5.54E-06 viral relapse MHC Candidate Top C T 0.2088 C T AX-11435436 rs3130532 HLA-C 6 31208453 0.669243 5.54E-06 viral relapse MHC Candidate Top A G 0.2088 A G AX-15354622 rs3130941 HLA-C 6 31197514 0.662868 7.75E-06 viral relapse MHC Candidate Top C G 0.2072 C G AX-11435434 rs3130528 HLA-C 6 31199460 0.598808 1.66E-05 viral relapse MHC Candidate Top T C 0.2115 T C AX-11435919 rs3134782 HLA-C 6 31197633 0.573613 1.68E-05 viral relapse MHC Candidate Top G A 0.221 G A AX-11435916 rs3134769 HLA-C 6 31205754 0.5054 7.72E-05 viral relapse MHC Candidate Top T C 0.3324 T C AX-11435432 rs3130521 HLA-C 6 31196376 0.510141 8.18E-05 viral relapse MHC Candidate Top T C 0.3287 T C AX-82884445 rs3130695 HLA-C 6 31211050 0.470284 0.000258 viral relapse MHC Candidate Top A G 0.3242 A G AX-15354633 rs3130685 HLA-C 6 31206206 -0.42529 0.00026 viral relapse MHC Candidate Top T C 0.4973 C T AX-15354698 rs2524119 HLA-C 6 31229404 0.380815 0.000772 viral relapse MHC Candidate Top T C 0.2869 T C AX-11435433 rs3130527 HLA-C 6 31198987 0.389965 0.003003 viral relapse MHC Candidate Top T C 0.2967 T C AX-11425411 rs2894186 HLA-C 6 31206868 -0.31881 0.008845 viral relapse MHC Candidate Top C G 0.4011 G C AX-50495706 rs3130439 HLA-C 6 31221023 -0.23878 0.015167 viral relapse MHC Candidate Top A G 0.5 G A AX-11433206 rs3095254 HLA-C 6 31221668 0.27173 0.01963 viral relapse MHC Candidate Top C G 0.3591 C G AX-11676201 rs9264189 HLA-C 6 31220163 0.249459 0.02553 viral relapse MHC Candidate Top A C 0.4282 A C AX-11389323 rs2394943 HLA-C 6 31220388 0.247638 0.025585 viral relapse MHC Candidate Top T C 0.4313 T C AX-11685437 rs9394047 HLA-C 6 31236250 -0.27896 0.031231 viral relapse MHC Candidate Top C A 0.2652 A C AX-11435538 rs3130948 HLA-C 6 31193523 -0.21961 0.032006 viral relapse MHC Candidate Top T C 0.3785 C T AX-15354704 rs9368666 HLA-C 6 31229644 -0.24909 0.045811 viral relapse MHC Candidate Top G A 0.275 A G AX-11435536 rs3130942 HLA-C 6 31197293 -0.25822 0.047561 viral relapse MHC Candidate Top T C 0.3956 C T AX-11435471 rs3130688 HLA-C 6 31210216 0.251956 0.049806 viral relapse MHC Candidate Top C T 0.4203 C T AX-11417845 rs3130536 HLA-C 6 31210532 0.251956 0.049806 viral relapse MHC Candidate Top A G 0.4203 A G AX-11435914 rs3134750 HLA-C 6 31218087 0.251956 0.049806 viral relapse MHC Candidate Top A G 0.4203 A G AX-11490436 rs4084090 HLA-C 6 31218835 -0.50926 0.029462 clinical recurrence MHC Candidate Bottom G A 0.1181 A G AX-35731063 rs9264127 HLA-C 6 31211592 -0.5527 0.030238 clinical recurrence MHC Candidate Bottom G C 0.1023 C G AX-11676190 rs9264039 HLA-C 6 31196591 -0.47866 0.040352 clinical recurrence MHC Candidate Bottom A G 0.1154 G A AX-11485919 rs3868078 HLA-C 6 31199164 -0.47866 0.040352 clinical recurrence MHC Candidate Bottom T C 0.1154 C T Table 4c SNP RSID Gene CHR POS estimated value P value reaction MAF risk pair gene protective pair AX-40474401 rs10426302 --- 19 55211547 0.451712561 0.000240387 viral relapse 0.3654 G A AX-32791043 rs59537494 MBOAT7 19 54688378 0.476837708 0.000678068 viral relapse 0.2198 G C AX-32793765 rs28366008 LILRB4 19 55174498 -0.513992692 0.000925382 viral relapse 0.1519 T C AX-32791067 rs36625 MBOAT7 19 54692523 0.355084386 0.001107075 viral relapse 0.4011 A G AX-11562447 rs635608 TSEN34 19 54696488 0.344914709 0.001176932 viral relapse 0.4643 C T AX-40473181 rs7595 TSEN34 19 54697079 0.344914709 0.001176932 viral relapse 0.4643 T C AX-83323675 rs731170 LILRB4 19 55176262 -0.468562637 0.001187372 viral relapse 0.239 G A AX-13455041 rs28513 --- 19 54699386 0.366160334 0.001868607 viral relapse 0.4973 C A AX-32795451 rs12459334 EPS8L1 19 55588726 0.533351627 0.003247705 viral relapse 0.1016 C T AX-51295385 rs11666535 --- 19 55217660 0.410213441 0.003485518 viral relapse 0.2639 G T AX-11527755 rs4806807 --- 19 55207900 0.359721702 0.004576148 viral relapse 0.3407 G T AX-40474407 rs11084367 --- 19 55213281 0.323708459 0.005596541 viral relapse 0.4973 G A AX-40473175 rs39714 MBOAT7 19 54693682 0.295723304 0.005852794 viral relapse 0.4536 C G AX-32795469 rs1654474 EPS8L1 19 55590594 0.496196364 0.006516564 viral relapse 0.1016 T C AX-11207928 rs12462907 GP6 19 55529100 0.24216561 0.006911051 viral relapse 0.306 T C AX-11643598 rs775893 NLRP2 19 55486167 -0.290614208 0.011613591 viral relapse 0.3352 C G AX-12388453 rs10416527 --- 19 55215632 0.287752966 0.012488897 viral relapse 0.4835 G A AX-11505772 rs4441391 --- 19 55216681 0.287752966 0.012488897 viral relapse 0.4835 G A AX-40473161 rs40167 MBOAT7 19 54682975 0.268925659 0.013809827 viral relapse 0.4836 G A AX-32792529 rs11084339 TTYH1 19 54948086 -0.444904956 0.014154957 viral relapse 0.1566 G A AX-40474775 rs775875 NLRP7 19 55446522 0.262662903 0.015424157 viral relapse 0.478 T A AX-40474665 rs2304225 FCAR 19 55385962 0.374671188 0.016022686 viral relapse 0.1806 G C AX-13454965 rs4077076 VSTM1 19 54558412 -0.286459718 0.018143745 viral relapse 0.2374 G A AX-40472901 rs4442924 VSTM1 19 54554942 0.356012339 0.018388072 viral relapse 0.1951 C A AX-11527741 rs4806527 KIR3DL1 19 55228948 -0.254093802 0.022274657 viral relapse 0.4836 G A AX-83135617 rs12608979 RDH13 19 55568084 0.377246744 0.022286121 viral relapse 0.1519 T C AX-11479003 rs3765013 COSV52557220 NCR1 19 55420801 -0.242495817 0.022506041 viral relapse 0.467 C A AX-40474663 rs12462181 --- 19 55385435 0.288971856 0.022787314 viral relapse 0.3022 C T AX-13455616 rs2075731 COSV52550169 KIR3DL3 19 55237616 0.258917784 0.02605448 viral relapse 0.4062 C T AX-32795291 rs12608988 RDH13 19 55567979 0.366644765 0.026168426 viral relapse 0.1511 A G AX-94351577 rs190480734 KIR2DL4 19 55307719 0.1850665 0.026403665 viral relapse 0.3825 A G AX-40475037 rs1654452 RDH13 19 55572284 0.322538925 0.026843638 viral relapse 0.1841 A G AX-32794129 rs11879415 KIR2DL4 19 55276380 -0.260151598 0.027476482 viral relapse 0.3861 C T AX-40473143 rs653560 TMC4 19 54677103 -0.246315381 0.028071892 viral relapse 0.4725 C G AX-40475023 rs11084387 RDH13 19 55565352 0.359882921 0.028445048 viral relapse 0.1538 A G AX-11166815 rs11672111 RDH13 19 55565634 0.359882921 0.028445048 viral relapse 0.1538 C G AX-40475027 rs10424969 RDH13 19 55566512 0.359882921 0.028445048 viral relapse 0.1538 G T AX-32792987 rs77389424 LAIR2 19 55028970 0.348600312 0.030102735 viral relapse 0.1243 C T AX-11477710 rs3745902 CM1111041 KIR3DL2 19 55378008 0.275803142 0.030573053 viral relapse 0.2995 T C AX-11166876 rs11672983 --- 19 55383051 0.275803142 0.030573053 viral relapse 0.2995 A G AX-40473637 rs17836364 LILRA4 19 54847587 -0.310174266 0.031362692 viral relapse 0.2238 G A AX-32794537 rs34549987 NCR1 19 55416954 -0.226798441 0.032477939 viral relapse 0.5 T C AX-40473405 rs11668526 RPS9 19 54749060 -0.320096266 0.032759469 viral relapse 0.2363 C T AX-11166583 rs11667105 NLRP2 19 55509865 0.215814943 0.03295294 viral relapse 0.2857 A G AX-40474339 rs1749282 --- 19 55194821 -0.238413105 0.034679844 viral relapse 0.3654 A G AX-11280328 rs1654660 --- 19 55195187 -0.238413105 0.034679844 viral relapse 0.3654 G A AX-13455605 rs73618328 KIR3DL1 19 55228122 -0.237775016 0.035164827 viral relapse 0.4808 T C AX-32794029 rs270785 KIR3DL1 19 55233850 0.315362658 0.035843002 viral relapse 0.239 T C AX-83521570 rs76522818 LILRB5 19 54755918 0.410121214 0.037299895 viral relapse 0.1126 G C AX-94364811 rs62131745 KIR3DL1 19 55234854 -0.228255819 0.038842978 viral relapse 0.4973 T C AX-40473651 rs2241384 LILRA4 19 54849942 0.275552297 0.040517637 viral relapse 0.2308 A G AX-12454687 rs1325158 KIR3DL1 19 55226402 0.238167326 0.041514617 viral relapse 0.4093 C T AX-11112044 rs10500318 KIR2DL4 19 55320779 0.333357496 0.042556048 viral relapse 0.1484 A G AX-11482916 rs3816051 --- 19 55385604 0.227606755 0.046660994 viral relapse 0.3674 C T AX-32794205 rs34508934 KIR2DL4 19 55311067 0.311133039 0.047553752 viral relapse 0.1456 A C AX-13455932 rs12460627 GP6 19 55529089 0.231413661 0.047739197 viral relapse 0.3764 C G AX-40473767 rs11667812 TTYH1 19 54913994 0.36934225 0.006864808 clinical recurrence 0.3819 G C AX-13455223 rs12974194 TTYH1 19 54914134 0.36934225 0.006864808 clinical recurrence 0.3819 T C AX-40473637 rs17836364 LILRA4 19 54847587 -0.478999864 0.007304168 clinical recurrence 0.2238 G A AX-40473755 rs11669431 TTYH1 19 54903416 -0.356897282 0.010503394 clinical recurrence 0.4341 A C AX-11234805 rs12984962 --- 19 54769205 -0.611762362 0.01597391 clinical recurrence 0.1264 T C AX-32791879 rs1761462 LILRA4 19 54824667 -0.400809784 0.021889851 clinical recurrence 0.2747 C T AX-32794831 rs4806464 NLRP2 19 55490720 -0.436542373 0.02288708 clinical recurrence 0.2155 T C AX-11442739 rs34190750 --- 19 55050562 0.308344304 0.022922586 clinical recurrence 0.3516 T C AX-32793975 rs28681595 LILRP2 19 55218126 0.353842095 0.02328333 clinical recurrence 0.2225 C T AX-94348052 rs12610675 TTYH1 19 54905393 0.29328675 0.024360008 clinical recurrence 0.4171 A G AX-32792425 rs12463051 TTYH1 19 54930952 -0.315289374 0.03099842 clinical recurrence 0.3956 G A AX-40474339 rs1749282 --- 19 55194821 -0.303231998 0.031723819 clinical recurrence 0.3654 A G AX-11280328 rs1654660 --- 19 55195187 -0.303231998 0.031723819 clinical recurrence 0.3654 G A AX-32795157 rs41275824 GP6 19 55543973 0.284695244 0.034010136 clinical recurrence 0.467 T C AX-40473651 rs2241384 LILRA4 19 54849942 0.342303097 0.037110016 clinical recurrence 0.2308 A G AX-11234761 rs12983338 --- 19 55210931 0.352021106 0.038636205 clinical recurrence 0.1566 C T AX-40474129 rs272408 LILRB1 19 55103603 0.328062285 0.041219535 clinical recurrence 0.3462 C T AX-40474859 rs10412569 NLRP2 19 55497855 -0.352993676 0.041637332 clinical recurrence 0.2335 A G AX-32794851 NLRP2 19 55493651 -0.352120385 0.045745286 clinical recurrence 0.228 C T AX-13455842 rs622941 NLRP7 19 55434458 -0.265313309 0.049245636 clinical recurrence 0.4669 C G AX-13455332 rs60690598 --- 19 55052198 0.297260211 0.049943394 clinical recurrence 0.2225 T C

HLA演化多樣性與復發之初發及持續臨床反應的關聯：I類(平均而言但亦獨立地對於A、B及C基因座中之各者)及II類區域(平均而言但亦獨立地對於DQB1、DPB1、DRB1基因座中之各者)中的高HLA演化多樣性係與病毒學復發之早期初發相關聯(可保護性抵抗)。Association of HLA evolutionary diversity with onset and sustained clinical response to relapse: Class I (on average but also independently for each of the A, B, and C loci) and Class II regions (on average but also independently High HLA evolutionary diversity in each of the DQB1, DPB1, DRB1 loci) is associated with early initiation of virological relapse (protective resistance).

平均I類及II類區域中之高HLA演化多樣性與持續臨床反應相關聯，且對於單獨HLA-C及HLA-DRB1基因座。High HLA evolutionary diversity in average class I and class II regions was associated with sustained clinical response, and for individual HLA-C and HLA-DRB1 loci.

平均II類中及HLA-A基因座之高HLA演化多樣性可保護性抵抗臨床復發之早期初發。所有結果概述於表5及圖7中。表5呈現與病毒學復發之早期初發、臨床復發之早期初發及持續臨床反應顯著(FDR＜10%)關聯的HLA HED區域的綜述。對於各基因座或區域，其對應模型中的估算值與未調整p值及錯誤發現率一同報告。指示保護因子(高演化多樣性)。 表5 分析 特徵 估算值 p 值 FDR 保護性 CR HED_MEANII_CAT_CR -0.63 0.00 0.04 高 CR HED_HLA_A_CAT_CR -0.56 0.01 0.09 高 SCR HED_MEANII_CAT_SCR 1.91 0.00 0.02 高 SCR HED_HLA_C_CAT_SCR 2.63 0.00 0.03 高 SCR HED_HLA_R_CAT_SCR 2.37 0.00 0.04 高 SCR HED_MEANI_CAT_SCR 1.19 0.01 0.08 高 VR HED_MEANII_CAT_VR -0.66 0.00 0.00 高 VR HED_MEANI_CAT_VR -0.79 0.01 0.07 高 VR HED_HLA_A_CAT_VR -0.43 0.01 0.07 高 VR HED_HLA_Q_CAT_VR -0.40 0.02 0.07 高 VR HED_HLA_B_CAT_VR -0.43 0.02 0.07 高 VR HED_HLA_C_CAT_VR -0.51 0.02 0.07 高 VR HED_HLA_P_CAT_VR -0.35 0.03 0.07 高 VR HED_HLA_R_CAT_VR -0.41 0.04 0.08 高 High HLA evolutionary diversity in average class II and HLA-A loci protects against early onset of clinical relapse. All results are summarized in Table 5 and Figure 7. Table 5 presents a summary of HLA HED regions associated with significant (FDR < 10%) early onset of virological relapse, early onset of clinical relapse, and sustained clinical response. For each locus or region, estimates from the corresponding model are reported along with the unadjusted p-value and false discovery rate. Indicates protective factor (high evolutionary diversity). table 5 analyze feature estimated value p -value FDR protective CR HED_MEANII_CAT_CR -0.63 0.00 0.04 high CR HED_HLA_A_CAT_CR -0.56 0.01 0.09 high SCR HED_MEANII_CAT_SCR 1.91 0.00 0.02 high SCR HED_HLA_C_CAT_SCR 2.63 0.00 0.03 high SCR HED_HLA_R_CAT_SCR 2.37 0.00 0.04 high SCR HED_MEANI_CAT_SCR 1.19 0.01 0.08 high VR HED_MEANII_CAT_VR -0.66 0.00 0.00 high VR HED_MEANI_CAT_VR -0.79 0.01 0.07 high VR HED_HLA_A_CAT_VR -0.43 0.01 0.07 high VR HED_HLA_Q_CAT_VR -0.40 0.02 0.07 high VR HED_HLA_B_CAT_VR -0.43 0.02 0.07 high VR HED_HLA_C_CAT_VR -0.51 0.02 0.07 high VR HED_HLA_P_CAT_VR -0.35 0.03 0.07 high VR HED_HLA_R_CAT_VR -0.41 0.04 0.08 high

如圖7A至C中所示，HLA演化多樣性(高vs.低，應用表3上定義之截止值)與病毒學復發之初發、臨床復發之初發及持續臨床反應著關聯。代表與病毒學復發之初發相關聯之HLA I類及II類之HED分數之卡普蘭-邁爾曲線顯示於圖7A及7B中。將代表高HED分數與持續臨床反應者之分佈關聯之條形圖添加至圖7A及7B (平均I類及平均II類)及圖7C (HLA-C及HLA-DRB1)。代表與臨床復發之初發相關聯之HLA II類及HLA-A之HED分數之卡普蘭-邁爾曲線顯示於圖7D中。As shown in Figures 7A-C, HLA evolutionary diversity (high vs. low, applying the cutoffs defined on Table 3) was associated with onset of virological relapse, onset of clinical relapse, and sustained clinical response. Kaplan-Meier curves representing HED scores for HLA class I and II associated with the onset of virological relapse are shown in Figures 7A and 7B. Bar graphs representing the distribution of high HED scores associated with sustained clinical responders were added to Figures 7A and 7B (Mean Class I and Mean Class II) and Figure 7C (HLA-C and HLA-DRB1). Kaplan-Meier curves representing HED scores for HLA class II and HLA-A associated with onset of clinical relapse are shown in Figure 7D.

HLA印記與臨床復發之初發的關聯：將治療中最後一次就診及治療方案時的HBsAg視為多變數模型中之主要效應。HLA-A及HLA II類區域中之高HLA演化多樣性均藉由模型比較識別為改良多變數模型中臨床復發之初發的預測。風險率將HbsAg量及治療方案作為主要效應，估算風險率報告於表7及圖8中。表7及圖8均展現臨床復發之Cox比例風險回歸分析，包括HLA-A區域及II類區域中之HED分數(獨立及一起)。對於各變數，風險率之估算值(大於/小於1)指示與復發之負/正關聯。Association of HLA signature with onset of clinical relapse: HBsAg at the last visit on treatment and regimen was considered as the main effect in a multivariate model. High HLA evolutionary diversity in both HLA-A and HLA class II regions was identified by model comparison as a predictor of onset of clinical recurrence in the modified multivariate model. Risk Ratios The estimated hazard ratios are reported in Table 7 and Figure 8, using HbsAg amount and treatment regimen as the main effects. Table 7 and Figure 8 both present Cox proportional hazards regression analysis for clinical recurrence, including HED scores in the HLA-A region and the class II region (independently and together). For each variable, an estimate of the hazard ratio (greater/less than 1) indicates a negative/positive association with recurrence.

藉由預測臨床復發之初發之ROC曲線之AUC比較多變數模型(不包括HLA HED分數，包括HLA-A區域及HLA II類區域中之HED分數(分開及一起))之性能(參見表6)。表6呈現多變數模型之間的性能的比較，該多變數模型包括HBsAg及方案作為主要效應，獨立或一起添加HLA-A區域及HLA-II類區域中之HED分數以預測臨床復發之初發：AIC、BIC、一致性及ROC AUC。The performance of multivariate models (excluding HLA HED scores, including HLA-A regions and HLA class II regions (separate and together)) was compared by AUC of the ROC curve for predicting the onset of clinical relapse (see Table 6 ). Table 6 presents a comparison of the performance between multivariate models including HBsAg and regimen as main effects, adding HED scores in HLA-A regions and HLA-II regions independently or together to predict onset of clinical relapse : AIC, BIC, Concordance and ROC AUC.

比較包括兩個區域之HLA HED分數之模型與包括僅臨床參數之模型，觀測到輕微改良。在停止治療之後兩年評估的對應於包括HLA HED分數的模型的時間相依性ROC曲線之AUC等於0.70，相比之下，包括僅治療結束HBsAg及治療方案的模型的時間相依性ROC曲線之AUC為0.67。 表6 模型 AIC BIC 一致性 AUC HBsAg + 方案 838.42 845.96 0.63 0.67 HBsAg + 方案 + HED_HLA_A_CAT_CR 832.39 842.44 0.66 0.7 HBsAg + 方案 + HED_MEANII_CAT_CR 835.14 845.18 0.65 0.69 HBsAg + 方案 + HED_HLA_A_CAT_CR + HED_MEANII_CAT_CR 830.31 842.87 0.67 0.7 表7 共變數 變數 HR 下限 上限 治療結束時的HBsAg (高vs低) HBSAG_CATHIGH 2.86 1.55 5.27 治療方案 (替諾福韋vs恩替卡韋) LAST_PR_CMTRTTENOFOVIR 1.94 1.28 2.96 HED HLA-A (高vs低) HED_HLA_A_CAT_CRHIGH 0.60 0.40 0.90 HED MEAN MHCII (高vs低) HED_MEANII_CAT_CRHIGH 0.58 0.39 0.87 A slight improvement was observed comparing the model including HLA HED scores for both regions to the model including only clinical parameters. The AUC corresponding to the time-dependent ROC curve for the model including HLA HED scores equal to 0.70, compared to the AUC for the time-dependent ROC curve for the model including only end-of-treatment HBsAg and treatment regimen, assessed two years after treatment discontinuation is 0.67. Table 6 Model AIC BIC consistency AUC HBsAg + protocol 838.42 845.96 0.63 0.67 HBsAg + Scheme + HED_HLA_A_CAT_CR 832.39 842.44 0.66 0.7 HBsAg + Scheme + HED_MEANII_CAT_CR 835.14 845.18 0.65 0.69 HBsAg + Scheme + HED_HLA_A_CAT_CR + HED_MEANII_CAT_CR 830.31 842.87 0.67 0.7 Table 7 covariate variable HR lower limit upper limit HBsAg at the end of treatment (high vs low) HBSAG_CATHIGH 2.86 1.55 5.27 Treatment options (tenofovir vs entecavir) LAST_PR_CMTRTTENOFOVIR 1.94 1.28 2.96 HED HLA-A (high vs low) HED_HLA_A_CAT_CRHIGH 0.60 0.40 0.90 HED MEAN MHCII (High vs Low) HED_MEANII_CAT_CRHIGH 0.58 0.39 0.87

HLA印記與病毒學復發之初發的關聯：將治療中最後一次就診及治療方案時的HBsAg視為多變數模型中之主要效應。Association of HLA signature with initial onset of virological relapse: HBsAg at last visit on treatment and regimen were considered as main effects in a multivariate model.

HLA-B*51及HLA-C*07，以及I類及II類區域中之高HLA演化多樣性藉由模型比較識別為改良多變數模型中病毒學復發之初發的預測。風險率將HBsAg量及治療方案視為主要效應，估算風險率報告於表9及圖9中。表9及圖9均展現病毒學復發之Cox比例風險回歸分析，包括HLA對偶基因B*51、HLA對偶基因C*07、HLA I類及II類區域中之HED分數。對於各變數，風險率之估算值(大於/小於1)指示與復發之負/正關聯。HLA-B*51 and HLA-C*07, and high HLA evolutionary diversity in class I and class II regions were identified by model comparison as predictors of onset of virological relapse in the modified multivariate model. Risk Rates HBsAg amount and treatment regimen were considered as main effects, and estimated risk rates are reported in Table 9 and Figure 9. Table 9 and Figure 9 both present Cox proportional hazards regression analysis of virological recurrence, including HED scores in HLA-dual B*51, HLA-dual C*07, HLA class I and II regions. For each variable, an estimate of the hazard ratio (greater/less than 1) indicates a negative/positive association with recurrence.

藉由預測病毒學復發之初發之ROC曲線之AUC比較多變數模型(包括HLA對偶基因、HLA HED分數(分開及一起))之性能與無HLA資訊之模型(表8)。表8呈現多變數模型之間的性能的比較，該多變數模型包括HBsAg及方案作為主要效應，獨立或一起添加HLA對偶基因B*51及C*07、HLA-I類及HLA-II類區域中之HED分數以預測病毒學復發之初發：AIC、BIC、一致性及ROC AUC。The performance of multivariate models (including HLA pair genes, HLA HED scores (separate and together)) was compared with models without HLA information (Table 8) by AUC of ROC curves for predicting the onset of virological relapse. Table 8 presents a comparison of performance between multivariate models including HBsAg and regimen as the main effects, independently or together with the addition of the HLA pair genes B*51 and C*07, HLA class I and HLA class II regions Among the HED scores to predict the onset of virological relapse: AIC, BIC, concordance and ROC AUC.

比較包括HLA HED分數及HLA對偶基因之模型與包括僅臨床參數之模型，觀測到明顯改良。在停止治療之後兩年評估的對應於包括HLA HED分數及HLA對偶基因的模型的時間相依性ROC曲線之AUC等於0.79，相比之下，包括僅治療結束HBsAg及治療方案的模型的時間相依性ROC曲線之AUC為0.66。 表8 模型 AIC BIC 一致性 AUC HBsAg + 方案 1188.76 1197.57 0.67 0.66 HBsAg + 方案 + B*51_計數 + C*07_計數 1167.99 1182.66 0.72 0.77 HBsAg + 方案 + HED_MEANI_CAT_VR + HED_MEANII_CAT_VR 1174.82 1189.49 0.71 0.73 HBsAg + 方案 + B*51_計數 + C*07_計數 + HED_MEANI_CAT_VR + HED_MEANII_CAT_VR 1158.27 1178.81 0.73 0.79 表9 共變數 變數 HR 下限 上限 治療結束時的HBsAg (高vs低) HBSAG_CATHIGH 1.66 1.06 2.59 治療方案 (替諾福韋vs恩替卡韋) LAST_PR_CMTRTTENOFOVIR 3.23 2.17 4.80 治療方案 (其他vs恩替卡韋) LAST_PR_CMTRTOTHER 2.38 1.19 4.79 B51 (ADD，更多vs更少) B51_計數 0.42 0.22 0.79 C07 (ADD，更多vs更少) C07_計數 1.75 1.27 2.42 HED MEAN MHCI  (高vs低) HED_MEANI_CAT_VRHIGH 0.41 0.20 0.81 HED MEAN MHCII (高vs低) HED_MEANII_CAT_VRHIGH 0.66 0.46 0.95 Comparing the model including HLA HED scores and HLA-pair genes to the model including clinical parameters only, significant improvement was observed. The AUC of the time-dependent ROC curve corresponding to the model including HLA HED scores and HLA-pair genes, assessed two years after treatment discontinuation, was equal to 0.79, compared to the time-dependence of the model including end-of-treatment HBsAg and treatment regimen only The AUC of the ROC curve was 0.66. Table 8 Model AIC BIC consistency AUC HBsAg + protocol 1188.76 1197.57 0.67 0.66 HBsAg + protocol + B*51_count+ C*07_count 1167.99 1182.66 0.72 0.77 HBsAg + Scheme + HED_MEANI_CAT_VR + HED_MEANII_CAT_VR 1174.82 1189.49 0.71 0.73 HBsAg + scheme + B*51_count + C*07_count + HED_MEANI_CAT_VR + HED_MEANII_CAT_VR 1158.27 1178.81 0.73 0.79 Table 9 covariate variable HR lower limit upper limit HBsAg at the end of treatment (high vs low) HBSAG_CATHIGH 1.66 1.06 2.59 Treatment options (tenofovir vs entecavir) LAST_PR_CMTRTTENOFOVIR 3.23 2.17 4.80 Treatment options (other vs entecavir) LAST_PR_CMTRTOTHER 2.38 1.19 4.79 B51 (ADD, more vs less) B51_count 0.42 0.22 0.79 C07 (ADD, more vs less) C07_Count 1.75 1.27 2.42 HED MEAN MHCI (High vs Low) HED_MEANI_CAT_VRHIGH 0.41 0.20 0.81 HED MEAN MHCII (High vs Low) HED_MEANII_CAT_VRHIGH 0.66 0.46 0.95

HLA印記與持續臨床反應的關聯：在多變數模型中將治療中最後一次就診時的HBsAg視為主要效應。比較包括HLA HED分數及HLA對偶基因之模型與包括僅臨床參數之模型，觀測到明顯改良。對應於包括HLA HED分數及HLA對偶基因之模型之ROC AUC值等於0.91，相比之下，包括僅治療結束HBsAg之模型之ROC AUC值為0.67 (表10)。表10呈現多變數模型之間的性能的比較，該多變數模型包括HBsAg作為主要效應，加上HLA對偶基因B*51及C*15計數，獨立或一起地加上HLA-I類及HLA-II類區域中之HED分數及HED HLA-C及HED HLA-DRB1，或僅加上HED HLA-I類及HED HLA-II類以預測持續臨床反應：AIC、BIC及ROC AUC。 表10 模型 AIC BIC AUC HBsAg 111.58 117.73 0.67 HBsAg + B51_計數 + C15_計數 103.44 115.74 0.79 HBsAg + HED_MEANI_CAT_SCR + HED_HLA_C_CAT_SCR + HED_MEANII_CAT_SCR + HED_HLA_R_CAT_SCR 89.66 108.11 0.87 HBsAg + B51_計數 + C15_計數 + HED_MEANI_CAT_SCR + HED_HLA_C_CAT_SCR + HED_MEANII_CAT_SCR + HED_HLA_R_CAT_SCR 87.24 111.84 0.91 HBsAg + B51_計數 + C15_計數 + HED_MEANI_CAT_SCR + HED_MEANII_CAT_SCR 89.95 108.41 0.89 Association of HLA signature with sustained clinical response: HBsAg at last visit on treatment was considered the main effect in a multivariate model. Comparing the model including HLA HED scores and HLA-pair genes to the model including clinical parameters only, significant improvement was observed. The ROC AUC value corresponding to the model including the HLA HED score and the HLA pair was equal to 0.91, compared to 0.67 for the model including only end-of-treatment HBsAg (Table 10). Table 10 presents a comparison of performance between multivariate models that included HBsAg as the main effect, plus HLA-dual genes B*51 and C*15 counts, independently or together, plus HLA-class I and HLA- HED scores and HED HLA-C and HED HLA-DRB1 in class II regions, or only HED HLA-class I and HED HLA-II were added to predict sustained clinical response: AIC, BIC and ROC AUC. Table 10 Model AIC BIC AUC HBsAg 111.58 117.73 0.67 HBsAg + B51_count + C15_count 103.44 115.74 0.79 HBsAg + HED_MEANI_CAT_SCR + HED_HLA_C_CAT_SCR + HED_MEANII_CAT_SCR + HED_HLA_R_CAT_SCR 89.66 108.11 0.87 HBsAg + B51_Count + C15_Count + HED_MEANI_CAT_SCR + HED_HLA_C_CAT_SCR + HED_MEANII_CAT_SCR + HED_HLA_R_CAT_SCR 87.24 111.84 0.91 HBsAg + B51_Count + C15_Count + HED_MEANI_CAT_SCR + HED_MEANII_CAT_SCR 89.95 108.41 0.89

有趣的是，包括HLA-B*51及HLA-C*15計數以及I類及II類區域之平均HED分數之模型給出極其相似的預測性能(BIC為108.41，相比之下，對於完整模型，BIC為111.84，獲得略低的AUC，為0.89，相比之下，對於完整模型，為0.91)。此最新模型之輸出概述於表11及圖10上。表11呈現持續臨床反應之邏輯回歸分析(估算優勢率及置信區間)，包括HLA對偶基因B*51、HLA對偶基因C*51、HLA I類及II類區域中之HED分數。圖10展現持續臨床反應之邏輯回歸分析，包括HLA對偶基因B*51、HLA對偶基因C*51、HLA I類及II類區域中之HED分數。對於各變數，優勢率之估算值(小於/大於1)指示與持續臨床反應之負/正關聯。 表11 共變數 變數 OR 下限 上限 治療結束時的HBsAg (高vs低) HBSAG_CATHIGH 0.09 0.02 0.33 B51 (ADD，更多vs更少) B51_計數 2.34 0.36 14.12 C15 (ADD，更多vs更少) C15_計數 7.68 1.29 46.66 HED MEAN MHCI (高vs低) HED_MEANI_CAT_SCRHIGH 5.38 1.51 21.62 HED MEAN MHCII (高vs低) HED_MEANII_CAT_SCRHIGH 11.49 3.08 57.35 Interestingly, models including HLA-B*51 and HLA-C*15 counts and mean HED scores for class I and class II regions gave very similar predictive performance (BIC of 108.41, compared to 108.41 for the full model). , with a BIC of 111.84, yielding a slightly lower AUC of 0.89, compared to 0.91 for the full model). The output of this latest model is summarized in Table 11 and Figure 10. Table 11 presents logistic regression analysis (estimated odds ratios and confidence intervals) for sustained clinical response, including HED scores in HLA-dual B*51, HLA-dual C*51, HLA class I and II regions. Figure 10 presents logistic regression analysis of sustained clinical response including HED scores in HLA-dual B*51, HLA-dual C*51, HLA class I and II regions. For each variable, an estimated odds ratio (less than/greater than 1) indicated a negative/positive association with sustained clinical response. Table 11 covariate variable OR lower limit upper limit HBsAg at the end of treatment (high vs low) HBSAG_CATHIGH 0.09 0.02 0.33 B51 (ADD, more vs less) B51_count 2.34 0.36 14.12 C15 (ADD, more vs less) C15_count 7.68 1.29 46.66 HED MEAN MHCI (High vs Low) HED_MEANI_CAT_SCRHIGH 5.38 1.51 21.62 HED MEAN MHCII (High vs Low) HED_MEANII_CAT_SCRHIGH 11.49 3.08 57.35

討論：在本大型前瞻性停止研究中，若干HLA I類對偶基因(或HLA-C區域中之SNP，如圖6D中所顯示，顯示相同顯著性)經顯示為預測病毒學復發之晚期初發及持續臨床反應。探索HLA對偶基因與慢性B型肝炎疾病之間的關聯的大多數研究集中於HLA II類區域(Wang等人，Journal of Immunology Research，2016，DOI:10.1155/2016/9069375；Singh，World Journal of Gastroenterology，2007，13: 1770)及與慢性感染及疾病進展之易感性的關聯。若已報告HLA-C 區域(與KIR區域一起)中之SNP與對IFN治療之反應之間的關聯(Khakoo，Science 2004，305: 872–4)，則據吾人所知，此為首次描述HLA I類區域在對NUC療法之長期反應(長達兩年而無病毒學復發)中起作用。HLA I類在長期抗病毒治療反應中在CHB中起作用的機制仍未知曉，但已報告二者藉由與自然殺手細胞相互作用及/或藉由向CD8陽性T細胞呈遞肽而在控制其他慢性感染中諸如在HCV (Khakoo，Science 2004，305: 872–4)及HIV (Science 2010；330: 1551–7)中起作用。在此定群中，可觀測到編碼與HLA-B及HLA-C蛋白相互作用之LILR配體及KIR配體之基因中的準時突變，表明抗原呈遞細胞的潛在作用及其與自然殺手細胞在長期反應中之相互作用。重要的是，在獨立定群中重現彼等觀測結果，且進一步探索彼等遺傳變異之功能後果。Discussion: In this large prospective stop study, several HLA class I dual genes (or SNPs in the HLA-C region, as shown in Figure 6D, showing the same significance) were shown to predict late-stage de novo virological relapse and sustained clinical response. Most studies exploring the association between HLA counterpart genes and chronic hepatitis B disease have focused on HLA class II regions (Wang et al., Journal of Immunology Research, 2016, DOI: 10.1155/2016/9069375; Singh, World Journal of Gastroenterology , 2007, 13: 1770) and its association with susceptibility to chronic infection and disease progression. If an association between SNPs in the HLA-C region (along with the KIR region) and response to IFN treatment has been reported (Khakoo, Science 2004, 305: 872-4), this is the first description of HLA to our knowledge Class I regions play a role in long-term response to NUC therapy (up to two years without virological relapse). The mechanism by which HLA class I functions in CHB in response to long-term antiviral therapy remains unknown, but both have been reported to control other It plays a role in chronic infections such as in HCV (Khakoo, Science 2004, 305: 872-4) and HIV (Science 2010; 330: 1551-7). In this cohort, punctual mutations in genes encoding LILR ligands and KIR ligands that interact with HLA-B and HLA-C proteins were observed, suggesting a potential role for antigen-presenting cells and their interaction with natural killer cells. Interactions in long-term responses. It is important to reproduce these observations in independent cohorts and to further explore the functional consequences of their genetic variation.

除了HLA I類對偶基因在長期治療反應中的此種主要作用之外，在此獨特定群中，顯示I類及II類區域中之高HLA演化多樣性可保護性抵抗病毒學復發之早期初發及預測持續臨床反應。在本研究中，HLA對偶基因雜合性與復發之初發無顯著關聯，而HLA I類及II類中的較大功能多樣性似乎是預測對直接抗病毒治療之長期反應。In addition to this major role of HLA class I counterpart genes in long-term treatment response, in this unique cohort, high HLA evolutionary diversity in class I and class II regions was shown to be protective against early initiation of virological relapse development and prediction of sustained clinical response. In the present study, HLA-dual gene heterozygosity was not significantly associated with the onset of relapse, whereas greater functional diversity in HLA classes I and II appeared to predict long-term response to direct-acting antiviral therapy.

HED (尤其是在I類區域中)的重要性早先已描述於對癌症中免疫療法之反應 (Chowell等人，Science，2018，359: 582–7；Chowell等人，Nature Medicine，2019，25: 1715–20)及HIV感染之控制 (Arora等人，Molecular Biology and Evolution，2020，37: 639–50；Carrington等人，Science 1999，283: 1748；Arora等人，Proceedings of the National Academy of Sciences of the United States of America 2019，116: 944–9)中，但尚未在對慢性HBV感染之抗病毒治療反應中進行探索。The importance of HEDs, especially in class I regions, has been previously described in response to immunotherapy in cancer (Chowell et al, Science, 2018, 359: 582-7; Chowell et al, Nature Medicine, 2019, 25: 1715-20) and control of HIV infection (Arora et al., Molecular Biology and Evolution, 2020, 37: 639-50; Carrington et al., Science 1999, 283: 1748; Arora et al., Proceedings of the National Academy of Sciences of the United States of America 2019, 116: 944–9), but has not been explored in response to antiviral therapy for chronic HBV infection.

兩個態樣(對偶基因優點及整體HLA功能多樣性)似乎顯著促進預測抗病毒治療反應且可用一種檢定(HLA分型)來測定，當考慮停止抑制治療時，此HLA印記可為預測患者結果中之有用貢獻者。Two aspects (dual gene advantage and overall HLA functional diversity) appear to significantly contribute to predicting antiviral treatment response and can be measured by an assay (HLA typing) that can predict patient outcome when discontinuation of suppressive therapy is considered useful contributors.

熟習此項技術者應理解，可對上文所描述的實施例作出改變而不脫離其廣泛發明概念。因此，應理解，本發明不限於所揭示的特定實施例，但意欲涵蓋於如由本描述所定義的本發明的精神及範疇內的修改。It will be understood by those skilled in the art that changes may be made to the embodiments described above without departing from the broad inventive concept thereof. Therefore, it is to be understood that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of this invention as defined by this description.

本文引用的所有文件均以引用之方式併入。All documents cited herein are incorporated by reference.

當結合附圖閱讀時，將更佳地理解前述總結以及本申請案之較佳實施例之以下詳細描述。然而，應理解，本申請案並不受限於顯示於附圖中之精確實施例。 The foregoing summary, as well as the following detailed description of preferred embodiments of the present application, will be better understood when read in conjunction with the accompanying drawings. It should be understood, however, that the application is not limited to the precise embodiments shown in the accompanying drawings.

圖1A及1B展示在治療停止之後病毒學復發(圖1A)及臨床復發(圖1B)之累積發生率，其藉由卡普蘭-邁爾(Kaplan-Meier)曲線進行評估。1A and 1B show the cumulative incidence of virological relapse (FIG. 1A) and clinical relapse (FIG. IB) after treatment cessation, as assessed by Kaplan-Meier curves.

圖2A及2B展示各HLA基因座之以兩位解析度(圖2A)及四位解析度(圖2B)觀測到的對偶基因的數量。2A and 2B show the number of dual genes observed at two-digit resolution (FIG. 2A) and four-digit resolution (FIG. 2B) for each HLA locus.

圖3A及3B展示在定群中各HLA基因座之針對各對偶基因以兩位解析度(圖3A)及四位解析度(圖3B)觀測到的HLA同合性的數量。Figures 3A and 3B show the number of HLA identities observed at two-digit resolution (Figure 3A) and four-digit resolution (Figure 3B) for each paired gene at each HLA locus in the population.

圖4表示概述研究定群中HED分數(每個基因座)之分佈的小提琴圖(violin plot)。包裹箱圖，代表每個基因座的中值HED分數(箱圖之極限代表第25及第75百分位數及晶鬚分別代表Q1及Q3加上1.5倍四分位間範圍)。Figure 4 presents a violin plot summarizing the distribution of HED scores (per locus) in the study population. Box plots representing the median HED scores for each locus (box plot limits represent the 25th and 75th percentiles and whiskers represent Q1 and Q3, respectively, plus 1.5 times the interquartile range).

圖5顯示與可加性(ADD)、顯性(DOM)及同合子(HOM)模型之與臨床復發(CR)、病毒學復發(VR)及持續臨床反應(SCR)之間的HLA對偶基因關聯之經FDR校正之p值。圖中的水平虛線對應於FDR 0.05及0.10。Figure 5 shows HLA paired genes with clinical relapse (CR), virological relapse (VR) and sustained clinical response (SCR) with additive (ADD), dominant (DOM) and homozygous (HOM) models The associated FDR-corrected p-values. The horizontal dashed lines in the graph correspond to FDRs of 0.05 and 0.10.

圖6A至E展示HLA對偶基因(兩位解析度)與病毒學復發之初發及/或持續臨床反應顯著關聯。如圖6A至6C中所示，B*51 (A)、C*07 (B)及C*15 (C)對偶基因之卡普蘭-邁爾曲線與病毒學復發之初發相關聯，及條形圖(barplot)代表持續臨床反應者體內B*51對偶基因(A) (圖6A)及C*15對偶基因(C) (圖6C)的存在或不存在之分佈。如圖6D中所示，HLA-C區域中之單核苷酸多型性(SNP)顯示相似顯著性水平(p值＜1e-6)，而測試與病毒學或臨床復發之初發之關聯作為候選方法。p值圖係相對於來自臨床復發之初發(頂部小圖)或病毒復發之初發(第2小圖)之GWAS關聯分析之基因組位置。各點對應於SNP之p值。標記指示對應於所獲得的最低p值之SNP之RS識別碼。如圖6E中所示，包括KIR配體的白血球受體複合物中的SNP (LRC區域定義於(GRCh37.p13)：CHR 19 54528888-55595686中)與病毒學及臨床復發之初發相關聯。p值圖係相對於來自臨床復發之初發(頂部小圖)或病毒復發之初發(第2小圖)之GWAS關聯分析之基因組位置。各點對應於SNP之p值。標記指示對應於10個最低p值之SNP之RS識別碼。中間小圖顯示使用r2作為度量的SNP對之間的連鎖不平衡。底部小圖提供包含在基因組區域19:54528888-55595686中之基因之綜述。基因跨越該區域以及axiom晶片(底部軌跡)上的SNP及染色體上的位置之覆蓋。Figures 6A-E show that HLA dual genes (two-digit resolution) are significantly associated with initial and/or sustained clinical response to virological relapse. As shown in Figures 6A-6C, Kaplan-Meier curves for the B*51 (A), C*07 (B), and C*15 (C) paired genes were associated with the onset of virological relapse, and bar The barplot represents the distribution of the presence or absence of the B*51 counterpart (A) (FIG. 6A) and the C*15 counterpart (C) (FIG. 6C) in sustained clinical responders. As shown in Figure 6D, single nucleotide polytypes (SNPs) in the HLA-C region showed similar levels of significance (p-value < le-6) while testing for association with onset of virological or clinical relapse as a candidate method. The p-values are plotted relative to genomic position from GWAS association analysis of clinical relapse (top panel) or viral relapse (2nd panel). Each point corresponds to the p-value of the SNP. The marker indicates the RS identifier of the SNP corresponding to the lowest p-value obtained. As shown in Figure 6E, SNPs in leukocyte receptor complexes including KIR ligands (LRC region defined in (GRCh37.p13): CHR 19 54528888-55595686) were associated with onset of virological and clinical relapse. The p-values are plotted relative to genomic position from GWAS association analysis of clinical relapse (top panel) or viral relapse (2nd panel). Each point corresponds to the p-value of the SNP. Labels indicate the RS identifiers of the SNPs corresponding to the 10 lowest p-values. The middle panel shows linkage disequilibrium between pairs of SNPs using r2 as a measure. The bottom panel provides an overview of the genes contained in the genomic region 19:54528888-55595686. The gene spans this region and coverage of SNPs and chromosomal locations on the axiom wafer (bottom trace).

圖7展示HLA演化多樣性與病毒學復發之初發、臨床復發之初發及持續臨床反應顯著關聯。代表與病毒學復發之初發相關聯之HLA I類及II類之HED分數之卡普蘭-邁爾曲線顯示於圖7A及7B中。將代表高HED分數與持續臨床反應者之分佈關聯之條形圖添加至圖7A及7B (平均I類及平均II類)及圖7C (HLA-C及HLA-DRB1)。代表與臨床復發之初發相關聯之HLA II類及HLA-A之HED分數之卡普蘭-邁爾曲線顯示於圖7D中。Figure 7 shows that HLA evolutionary diversity is significantly associated with onset of virological relapse, onset of clinical relapse, and sustained clinical response. Kaplan-Meier curves representing HED scores for HLA class I and II associated with the onset of virological relapse are shown in Figures 7A and 7B. Bar graphs representing the distribution of high HED scores associated with sustained clinical responders were added to Figures 7A and 7B (Mean Class I and Mean Class II) and Figure 7C (HLA-C and HLA-DRB1). Kaplan-Meier curves representing HED scores for HLA class II and HLA-A associated with onset of clinical relapse are shown in Figure 7D.

圖8展示臨床復發之Cox比例風險回歸分析，包括HLA-A區域及HLA II類區域之HLA HED分數。對於各變數，風險率之估算值(大於/小於1)指示與復發之負/正關聯。Figure 8 shows Cox proportional hazards regression analysis of clinical recurrence, including HLA HED scores for HLA-A regions and HLA class II regions. For each variable, an estimate of the hazard ratio (greater/less than 1) indicates a negative/positive association with recurrence.

圖 9展示病毒學復發之Cox比例風險回歸分析，包括HLA對偶基因B*51、HLA對偶基因C*07、HLA I類及II類區域中之HED分數。對於各變數，風險率之估算值(大於/小於1)指示與復發之負/正關聯。 Figure 9 shows Cox proportional hazards regression analysis of virological recurrence, including HED scores in the HLA-dual gene B*51, HLA-dual gene C*07, HLA class I and II regions. For each variable, an estimate of the hazard ratio (greater/less than 1) indicates a negative/positive association with recurrence.

圖 10展示持續臨床反應之邏輯回歸分析，包括HLA對偶基因B*51、HLA對偶基因C*51、HLA I類及II類區域中之HED分數。對於各變數，優勢率之估算值(小於/大於1)指示與持續臨床反應之負/正關聯。 Figure 10 shows logistic regression analysis of sustained clinical response including HED scores in HLA-dual B*51, HLA-dual C*51, HLA class I and II regions. For each variable, an estimated odds ratio (less than/greater than 1) indicated a negative/positive association with sustained clinical response.

Claims (49)

一種判定患有慢性B型肝炎(CHB)感染的個體在病毒抑制治療中止之後是否具有高或低復發機率、較佳地在中止之後兩年時間內是否具有高或低復發機率之方法，該方法包括： a. 偵測從該個體獲得的生物樣本中該CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i.     HLA演化多樣性(HED)分數； ii.    人類白血球抗原(HLA)對偶基因； iii.   一或多個HLA-C單核苷酸多型性(SNPs)；及 iv.    白血球受體複合物(LCR) SNPs； b. 若在該生物樣本中偵測到該一或多個免疫遺傳生物標記，則判定該個體之復發機率為低，或若在該生物樣本中未偵測到該等免疫遺傳生物標記，則判定該個體之復發機率為高。 A method of determining whether an individual suffering from chronic hepatitis B (CHB) infection has a high or low chance of relapse after discontinuation of viral suppression therapy, preferably within two years after discontinuation, the method include: a. Detecting the presence of one or more immunogenetic biomarkers of viral control of the CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. HLA Evolutionary Diversity (HED) score; ii. Human leukocyte antigen (HLA) pair gene; iii. One or more HLA-C single nucleotide polytypes (SNPs); and iv. Leukocyte receptor complex (LCR) SNPs; b. If the one or more immunogenetic biomarkers are detected in the biological sample, the probability of recurrence of the individual is determined to be low, or if the immunogenetic biomarkers are not detected in the biological sample, then The individual is judged to have a high probability of recurrence. 一種治療有需要個體中慢性B型肝炎(CHB)感染之方法，該方法包括： d. 對該個體投與病毒抑制治療以治療該CHB感染； e. 偵測從該個體獲得的生物樣本中該CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： v.     HLA演化多樣性(HED)分數； vi.    人類白血球抗原(HLA)對偶基因； vii.   一或多個HLA-C單核苷酸多型性(SNPs)；及 viii. 白血球受體複合物(LCR) SNPs； f. 若在該生物樣本中偵測到步驟b之該一或多個免疫遺傳生物標記，一旦達成病毒抑制則中止該病毒抑制治療，較佳地，該病毒抑制治療係在治療2年之後中止；或 若在該生物樣本中未偵測到步驟b之免疫遺傳生物標記，則繼續該病毒抑制治療，甚至在達成病毒抑制之後，及/或對該個體投與另外或不同病毒抑制治療。 A method of treating chronic hepatitis B (CHB) infection in an individual in need thereof, the method comprising: d. administering to the individual viral suppressive therapy to treat the CHB infection; e. Detecting the presence of one or more immunogenetic biomarkers for viral control of the CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: v. HLA Evolutionary Diversity (HED) score; vi. Human leukocyte antigen (HLA) pair gene; vii. One or more HLA-C single nucleotide polytypes (SNPs); and viii. Leukocyte receptor complex (LCR) SNPs; f. If the one or more immunogenetic biomarkers of step b are detected in the biological sample, the viral suppression therapy is discontinued once viral suppression is achieved, preferably, the viral suppressive therapy is discontinued after 2 years of treatment ;or If the immunogenetic biomarker of step b is not detected in the biological sample, the viral suppression therapy is continued, even after viral suppression is achieved, and/or additional or different viral suppression therapy is administered to the individual. 一種治療有需要個體中慢性B型肝炎(CHB)感染之方法，該方法包括： e. 對該個體投與病毒抑制治療以治療該CHB感染； f. 偵測從該個體獲得的生物樣本中該CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i.    HLA演化多樣性(HED)分數； ii.   人類白血球抗原(HLA)對偶基因； iii. 一或多個HLA-C單核苷酸多型性(SNPs)；及 iv.   白血球受體複合物(LCR) SNPs； g.    當該個體中該CHB感染抑制時，中止該病毒抑制治療，及 h.    若在該生物樣本中未偵測到免疫遺傳生物標記，則在中止之後少於兩年對該個體投與病毒抑制治療或另一病毒抑制治療。 A method of treating chronic hepatitis B (CHB) infection in an individual in need thereof, the method comprising: e. administering to the individual viral suppressive therapy to treat the CHB infection; f. Detecting the presence of one or more immunogenetic biomarkers of viral control of the CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. HLA Evolutionary Diversity (HED) score; ii. Human leukocyte antigen (HLA) pair gene; iii. One or more HLA-C single nucleotide polytypes (SNPs); and iv. Leukocyte receptor complex (LCR) SNPs; g. Discontinue the viral suppression therapy when the CHB infection is suppressed in the individual, and h. If no immunogenetic biomarker is detected in the biological sample, administer viro-suppressive therapy or another viro-suppressive therapy to the individual less than two years after discontinuation. 如請求項1至3中任一項之方法，其中該免疫遺傳生物標記包含HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在。The method of any one of claims 1 to 3, wherein the immunogenetic biomarker comprises the presence of HLA counterpart B*51 or C*15 or the absence of HLA counterpart C*07. 如請求項1至4中任一項之方法，其中該免疫遺傳生物標記包含選自由以下組成之群之HLA-C SNP：rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、rs9264039及rs3868078，或其互補序列。The method of any one of claims 1 to 4, wherein the immunogenetic biomarker comprises an HLA-C SNP selected from the group consisting of: rs2394952, rs3130542, rs2894202, rs9264523, rs1049281, rs9264643, rs1130838, rs2394888, AX- 83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、 rs3130536, rs3134750, rs4084090, rs9264127, rs9264039 and rs3868078, or their complements. 如請求項1至5中任一項之方法，其中該免疫遺傳生物標記包含至少一個大於選自下表之臨限值之HED分數： HLA 區域 HLA 基因 變數 臨限值 平均HLA I類 HLA-A HED_HLA_A_CAT_VR 3.88 平均HLA I類 HLA-B HED_HLA_B_CAT_VR 9.37 平均HLA I類 HLA-C HED_HLA_C_CAT_VR 0.00 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_VR 8.69 平均HLA II類 HLA-DPB1 HED_HLA_P_CAT_VR 2.21 平均HLA II類 HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_VR 12.68 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_VR 7.55 平均HLA I類 HLA-A HED_HLA_A_CAT_CR 3.88 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_CR 7.67 平均HLA I類 HLA-C HED_HLA_C_CAT_SCR 7.37 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_SCR 7.61 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_SCR 8.21
。 The method of any one of claims 1 to 5, wherein the immunogenetic biomarker comprises at least one HED score greater than a threshold value selected from the following table: HLA region HLA gene variable Threshold value Average HLA class I HLA-A HED_HLA_A_CAT_VR 3.88 Average HLA class I HLA-B HED_HLA_B_CAT_VR 9.37 Average HLA class I HLA-C HED_HLA_C_CAT_VR 0.00 Average HLA class I MEAN_MHCI HED_MEANI_CAT_VR 8.69 Average HLA class II HLA-DPB1 HED_HLA_P_CAT_VR 2.21 Average HLA class II HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_VR 12.68 Average HLA class II MEAN_MHCII HED_MEANII_CAT_VR 7.55 Average HLA class I HLA-A HED_HLA_A_CAT_CR 3.88 Average HLA class II MEAN_MHCII HED_MEANII_CAT_CR 7.67 Average HLA class I HLA-C HED_HLA_C_CAT_SCR 7.37 Average HLA class I MEAN_MHCI HED_MEANI_CAT_SCR 7.61 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 Average HLA class II MEAN_MHCII HED_MEANII_CAT_SCR 8.21
. 如請求項1至6中任一項之方法，其中該免疫遺傳生物標記包含選自由以下組成之群之LCR SNP：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598，或其互補序列。The method of any one of claims 1 to 6, wherein the immunogenetic biomarker comprises an LCR SNP selected from the group consisting of rs10426302, rs59537494, rs28366008, rs36625, rs635608, rs7595, rs731170, rs28513, rs12459334, rs11666535, rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、 rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、 rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598，或其互補序列。 如請求項1至7中任一項之方法，該方法進一步包括測定該個體之生物樣本中HBV DNA、丙胺酸轉胺酶(ALT)及B型肝炎e抗原(HBeAg)中之至少一者之量。The method of any one of claims 1 to 7, further comprising determining at least one of HBV DNA, alanine transaminase (ALT), and hepatitis B e antigen (HBeAg) in a biological sample of the individual quantity. 如請求項1至8中任一項之方法，其中該病毒抑制治療包括對該個體投與治療有效量之核苷酸或核苷類似物(NUC)。The method of any one of claims 1 to 8, wherein the viral suppressive treatment comprises administering to the individual a therapeutically effective amount of a nucleotide or nucleoside analog (NUC). 如請求項1至9中任一項之方法，其中該一或多個HLA-C SNP係選自由以下組成之群：rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750，或其互補序列。The method of any one of claims 1 to 9, wherein the one or more HLA-C SNPs are selected from the group consisting of: rs2394952, rs3130542, rs2894202, rs9264523, rs1049281, rs9264643, rs1130838, rs2394888, AX-83089411 、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536 and rs3134750, or its complement. 如請求項1至9中任一項之方法，其中該一或多個HLA-C SNP係選自由rs4084090、rs9264127、rs9264039及rs3868078或其互補序列組成之群。The method of any one of claims 1 to 9, wherein the one or more HLA-C SNPs are selected from the group consisting of rs4084090, rs9264127, rs9264039 and rs3868078 or their complements. 如請求項1至11中任一項之方法，其中該HED分數係選自由HED HLA-A大於3.88之值、HED HLA-B大於9.37之值、HED HLA-C大於0.00之值、平均HED HLA I類大於8.69之值、HED HLA-DPB1大於2.21之值、HED HLA-DQB1大於11.98之值、HED HLA-DRB1大於12.68之值及平均HED HLA II類大於7.55之值組成之群。The method of any one of claims 1 to 11, wherein the HED score is selected from a value of HED HLA-A greater than 3.88, a value of HED HLA-B greater than 9.37, a value of HED HLA-C greater than 0.00, average HED HLA Group I with values greater than 8.69, HED HLA-DPB1 greater than 2.21, HED HLA-DQB1 greater than 11.98, HED HLA-DRB1 greater than 12.68 and average HED HLA class II values greater than 7.55. 如請求項1至11中任一項之方法，其中該HED分數係選自由HED HLA-A大於3.88之值及平均HED HLA II類大於7.67之值組成之群。The method of any one of claims 1 to 11, wherein the HED score is selected from the group consisting of a HED HLA-A value greater than 3.88 and a mean HED HLA class II value greater than 7.67. 如請求項1至11中任一項之方法，其中該HED分數係選自由HED HLA-C大於7.37之值、平均HED HLA I類大於7.61之值、HED HLA-DRB1大於14.16之值及平均HED HLA II類大於8.21之值組成之群。The method of any one of claims 1 to 11, wherein the HED score is selected from the group consisting of HED HLA-C greater than 7.37, mean HED HLA class I greater than 7.61, HED HLA-DRB1 greater than 14.16, and mean HED Group consisting of HLA class II values greater than 8.21. 如請求項1至14中任一項之方法，其中該一或多個LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627，或其互補序列。The method of any one of claims 1 to 14, wherein the one or more LCR SNPs are selected from the group consisting of rs10426302, rs59537494, rs28366008, rs36625, rs635608, rs7595, rs731170, rs28513, rs12459334, rs11666535, rs4806807 、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560 、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627，或其互補sequence. 如請求項1至14中任一項之方法，其中該一或多個LCR SNP係選自由以下組成之群：rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598，或其互補序列。The method of any one of claims 1 to 14, wherein the one or more LCR SNPs are selected from the group consisting of: rs11667812, rs12974194, rs17836364, rs11669431, rs12984962, rs1761462, rs4806464, rs34190750, rs28681595, rs12610675 , rs1749282, rs1654660, rs41275824, rs2241384, rs12983338, rs272408, rs10412569, AX-3232794851, rs622941 and rs60690598, or their complements. 如請求項1至16中任一項之方法，其中該SNP或對偶基因係藉由選自由以下組成之群之方法來判定：DNA定序、限制片段長度多型性(RFLP分析)、對偶基因特異性寡核苷酸(ASO)分析、變性/溫度梯度凝膠電泳(DGGE/TGGE)、單股構象多型性(SSCP)分析、雙去氧指紋分析(ddF)、焦磷酸定序分析、acycloprime分析、反向墨點轉漬(Reverse dot blot)、基因晶片(GeneChip)微陣列、動態對偶基因特異性雜交(DASH)、肽核酸(PNA)及鎖核酸(LNA)探針、TaqMan、分子信標(Molecular Beacons)、嵌入染料(Intercalating dye)、FRET引子、AlphaScreen、SNPstream、遺傳位元分析(GBA)、多重微定序、SNaPshot、MassEXTEND、MassArray、GOOD檢定、微陣列微定序(Microarray miniseq)、陣列式引子延伸(APEX)、微陣列引子延伸、標籤陣列(Tag arrays)、經編碼之微球(Coded microspheres)、模板導向併入(TDI)、螢光偏振、比色寡核苷酸連接檢定(OLA)、序列編碼OLA (Sequence-coded OLA)、微陣列連接、連接酶鏈反應、扣鎖(Padlock)探針、滾環擴增(Rolling circle amplification)，及侵入物(Invader)檢定。The method of any one of claims 1 to 16, wherein the SNP or counterpart is determined by a method selected from the group consisting of DNA sequencing, restriction fragment length polymorphism (RFLP analysis), counterpart Specific Oligonucleotide (ASO) Analysis, Denaturing/Temperature Gradient Gel Electrophoresis (DGGE/TGGE), Single Strand Conformation Polymorphism (SSCP) Analysis, Dideoxy Fingerprinting (ddF), Pyrosequencing Analysis, acycloprime assay, Reverse dot blot, GeneChip microarray, Dynamic Dual Gene-Specific Hybridization (DASH), Peptide Nucleic Acid (PNA) and Locked Nucleic Acid (LNA) Probes, TaqMan, Molecular Molecular Beacons, Intercalating dyes, FRET primers, AlphaScreen, SNPstream, Genetic Bit Analysis (GBA), Multiplex Microsequencing, SNaPshot, MassEXTEND, MassArray, GOOD Assay, Microarray Microsequencing miniseq), Arrayed Primer Extension (APEX), Microarray Primer Extension, Tag arrays, Coded microspheres, Template Directed Incorporation (TDI), Fluorescence Polarization, Colorimetric Oligonucleotides Acid ligation assay (OLA), Sequence-coded OLA (Sequence-coded OLA), microarray ligation, ligase chain reaction, Padlock probe, Rolling circle amplification, and Invader Check. 如請求項1至17中任一項之方法，其中該病毒抑制劑係核苷酸或核苷類似物(NUC)，及該NUC係選自由替諾福韋(tenofovir)、恩替卡韋(entecavir)、拉米夫定(lamivudine)、阿德福韋(adefovir)及替比夫定(telbivudine)組成之群。The method of any one of claims 1 to 17, wherein the viral inhibitor is a nucleotide or nucleoside analog (NUC), and the NUC is selected from the group consisting of tenofovir, entecavir, A group consisting of lamivudine, adefovir and telbivudine. 如請求項1至18中任一項之方法，其中，當該個體達成HBV DNA ＜ 60 IU/mL、丙胺酸轉胺酶(ALT) ＜ 80 U/L及B型肝炎e抗原(HBeAg)陰性中之至少一者時，該個體中止該病毒抑制治療。The method of any one of claims 1 to 18, wherein when the individual achieves HBV DNA < 60 IU/mL, alanine aminotransferase (ALT) < 80 U/L and hepatitis B e antigen (HBeAg) negative At least one of these, the subject discontinues the viral suppressive therapy. 如請求項19之方法，其中該個體於該病毒抑制治療中止之時進一步達成HBsAg ＜ 100 IU/mL。The method of claim 19, wherein the subject further achieves HBsAg < 100 IU/mL upon discontinuation of the viral suppressive therapy. 如請求項1至20中任一項之方法，其中該個體在中止該病毒抑制治療之後的3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後沒有病毒學復發，且該病毒學復發經識別為HBV DNA ≥ 2000 IU/ml或HBeAg陽性。The method of any one of claims 1 to 20, wherein the subject is 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months after discontinuation of the viral suppression therapy, or a period in between. There was no virological relapse at or after any time and the virological relapse was identified as HBV DNA ≥ 2000 IU/ml or HBeAg positive. 如請求項1至20中任一項之方法，其中該個體在中止該病毒抑制治療之後的3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間或之後沒有臨床復發，且該臨床復發經識別為i) HBV DNA ≥ 2000 IU/ml或HBeAg陽性，且ii) ALT ≥ 80 U/L。The method of any one of claims 1 to 20, wherein the subject is 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months after discontinuation of the viral suppression therapy, or a period in between. There was no clinical relapse at any time or after, and the clinical relapse was identified as i) HBV DNA ≥ 2000 IU/ml or HBeAg positive, and ii) ALT ≥ 80 U/L. 如請求項1至22中任一項之方法，其中該生物樣本係組織樣本、細胞樣本或血液樣本。The method of any one of claims 1 to 22, wherein the biological sample is a tissue sample, a cell sample or a blood sample. 一種病毒抑制治療，特別是包含核苷酸或核苷類似物(NUC)之病毒抑制治療，更特別是包含選自由替諾福韋、恩替卡韋、拉米夫定、阿德福韋及替比夫定組成之群之NUC之病毒抑制治療，其用於治療有需要個體中慢性B型肝炎病毒(CHB)感染，其中該治療包括： a. 對該個體投與病毒抑制治療以治療CHB感染； b. 偵測從該個體獲得的生物樣本中該CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i.     HLA演化多樣性(HED)分數； ii.    人類白血球抗原(HLA)對偶基因； iii.   一或多個HLA-C單核苷酸多型性(SNPs)；及 iv.    白血球受體複合物(LCR) SNPs； c. 若在該生物樣本中偵測到步驟b之該一或多個免疫遺傳生物標記，一旦達成病毒抑制則中止該病毒抑制治療，較佳地，該病毒抑制治療係在治療2年之後中止；或 若在該生物樣本中未偵測到步驟b之免疫遺傳生物標記，則繼續該病毒抑制治療，甚至在達成病毒抑制之後，及/或對該個體投與另外或不同病毒抑制治療。 A viral suppressive treatment, particularly a viral suppressive treatment comprising a nucleotide or nucleoside analog (NUC), more particularly comprising a treatment selected from the group consisting of tenofovir, entecavir, lamivudine, adefovir and telbiv Viral suppressive therapy of a grouped NUC for the treatment of chronic hepatitis B virus (CHB) infection in an individual in need thereof, wherein the therapy comprises: a. administering to the individual viral suppressive therapy to treat CHB infection; b. Detecting the presence of one or more immunogenetic biomarkers for viral control of the CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. HLA Evolutionary Diversity (HED) score; ii. Human leukocyte antigen (HLA) pair gene; iii. One or more HLA-C single nucleotide polytypes (SNPs); and iv. Leukocyte receptor complex (LCR) SNPs; c. If the one or more immunogenetic biomarkers of step b are detected in the biological sample, the viral suppression therapy is discontinued once viral suppression is achieved, preferably, the viral suppressive therapy is discontinued after 2 years of treatment ;or If the immunogenetic biomarker of step b is not detected in the biological sample, the viral suppression therapy is continued, even after viral suppression is achieved, and/or additional or different viral suppression therapy is administered to the individual. 一種病毒抑制治療，特別是包含核苷酸或核苷類似物(NUC)之病毒抑制治療，更特別是包含選自由替諾福韋、恩替卡韋、拉米夫定、阿德福韋及替比夫定組成之群之NUC之病毒抑制治療，其用於治療有需要個體中慢性B型肝炎病毒(CHB)感染，其中該治療包括： a. 對該個體投與病毒抑制治療以治療CHB感染； b. 在從該個體獲得的生物樣本中偵測CHB感染之病毒控制之一或多個免疫遺傳生物標記的存在，其中該一或多個免疫遺傳生物標記係選自由下列組成之群： i.     HLA演化多樣性(HED)分數； ii.    人類白血球抗原(HLA)對偶基因； iii.   一或多個HLA-C單核苷酸多型性(SNPs)；及 iv.    白血球受體複合物(LCR) SNPs； c. 當該個體中CHB感染抑制時，中止該病毒抑制治療，及 d. 若在該生物樣本中未偵測到免疫遺傳生物標記，則在該中止之後少於兩年對該個體投與病毒抑制治療或另一病毒抑制治療。 A viral suppressive treatment, particularly a viral suppressive treatment comprising a nucleotide or nucleoside analog (NUC), more particularly comprising a treatment selected from the group consisting of tenofovir, entecavir, lamivudine, adefovir and telbiv Viral suppressive therapy of a grouped NUC for the treatment of chronic hepatitis B virus (CHB) infection in an individual in need thereof, wherein the therapy comprises: a. administering to the individual viral suppressive therapy to treat CHB infection; b. Detecting the presence of one or more immunogenetic biomarkers for viral control of CHB infection in a biological sample obtained from the individual, wherein the one or more immunogenetic biomarkers are selected from the group consisting of: i. HLA Evolutionary Diversity (HED) score; ii. Human leukocyte antigen (HLA) pair gene; iii. One or more HLA-C single nucleotide polytypes (SNPs); and iv. Leukocyte receptor complex (LCR) SNPs; c. Discontinue viral suppression therapy when CHB infection is suppressed in the individual, and d. If no immunogenetic biomarker is detected in the biological sample, administer viro-suppressive therapy or another viro-suppressive therapy to the individual less than two years after the discontinuation. 如請求項24至25中任一項之病毒抑制治療，其中該免疫遺傳生物標記包含HLA對偶基因B*51或C*15的存在或HLA對偶基因C*07的不存在。The viral suppression therapy of any one of claims 24 to 25, wherein the immunogenetic biomarker comprises the presence of HLA counterpart B*51 or C*15 or the absence of HLA counterpart C*07. 如請求項24至26中任一項之病毒抑制治療，其中該免疫遺傳生物標記包含選自由以下組成之群之HLA-C SNP：rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536、rs3134750、rs4084090、rs9264127、rs9264039及rs3868078，或其互補序列。The viral suppression therapy of any one of claims 24 to 26, wherein the immunogenetic biomarker comprises an HLA-C SNP selected from the group consisting of rs2394952, rs3130542, rs2894202, rs9264523, rs1049281, rs9264643, rs1130838, rs2394888, AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、 rs3130688, rs3130536, rs3134750, rs4084090, rs9264127, rs9264039 and rs3868078, or their complements. 如請求項24至27中任一項之病毒抑制治療，其中該免疫遺傳生物標記包含至少一個大於選自下表之臨限值之HED分數： HLA 區域 HLA 基因 變數 臨限值 平均HLA I類 HLA-A HED_HLA_A_CAT_VR 3.88 平均HLA I類 HLA-B HED_HLA_B_CAT_VR 9.37 平均HLA I類 HLA-C HED_HLA_C_CAT_VR 0.00 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_VR 8.69 平均HLA II類 HLA-DPB1 HED_HLA_P_CAT_VR 2.21 平均HLA II類 HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_VR 12.68 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_VR 7.55 平均HLA I類 HLA-A HED_HLA_A_CAT_CR 3.88 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_CR 7.67 平均HLA I類 HLA-C HED_HLA_C_CAT_SCR 7.37 平均HLA I類 MEAN_MHCI HED_MEANI_CAT_SCR 7.61 平均HLA II類 HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 平均HLA II類 MEAN_MHCII HED_MEANII_CAT_SCR 8.21
。 The viral suppression therapy of any one of claims 24 to 27, wherein the immunogenetic biomarker comprises at least one HED score greater than a threshold value selected from the following table: HLA region HLA gene variable Threshold value Average HLA class I HLA-A HED_HLA_A_CAT_VR 3.88 Average HLA class I HLA-B HED_HLA_B_CAT_VR 9.37 Average HLA class I HLA-C HED_HLA_C_CAT_VR 0.00 Average HLA class I MEAN_MHCI HED_MEANI_CAT_VR 8.69 Average HLA class II HLA-DPB1 HED_HLA_P_CAT_VR 2.21 Average HLA class II HLA-DQB1 HED_HLA_Q_CAT_VR 11.98 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_VR 12.68 Average HLA class II MEAN_MHCII HED_MEANII_CAT_VR 7.55 Average HLA class I HLA-A HED_HLA_A_CAT_CR 3.88 Average HLA class II MEAN_MHCII HED_MEANII_CAT_CR 7.67 Average HLA class I HLA-C HED_HLA_C_CAT_SCR 7.37 Average HLA class I MEAN_MHCI HED_MEANI_CAT_SCR 7.61 Average HLA class II HLA-DRB1 HED_HLA_R_CAT_SCR 14.16 Average HLA class II MEAN_MHCII HED_MEANII_CAT_SCR 8.21
. 如請求項24至28中任一項之病毒抑制治療，其中該免疫遺傳生物標記包含選自由以下組成之群之LCR SNP：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598，或其互補序列。The viral suppression therapy of any one of claims 24 to 28, wherein the immunogenetic biomarker comprises an LCR SNP selected from the group consisting of: rs10426302, rs59537494, rs28366008, rs36625, rs635608, rs7595, rs731170, rs28513, rs12459334, rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、 rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934、rs12460627、 rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598，或其互補序列。 如請求項24至29中任一項之病毒抑制治療，其中該病毒抑制治療進一步包括測定該個體之生物樣本中HBV DNA、丙胺酸轉胺酶(ALT)及B型肝炎e抗原(HBeAg)中之至少一者之量。The viral suppression therapy of any one of claims 24 to 29, wherein the viral suppression therapy further comprises measuring HBV DNA, alanine transaminase (ALT) and hepatitis B e antigen (HBeAg) in a biological sample of the individual the amount of at least one of them. 如請求項24至30中任一項之病毒抑制治療，其中該病毒抑制治療包括對該個體投與治療有效量之核苷酸或核苷類似物(NUC)。The viral suppression therapy of any one of claims 24 to 30, wherein the viral suppression therapy comprises administering to the individual a therapeutically effective amount of a nucleotide or nucleoside analog (NUC). 如請求項24至31中任一項之病毒抑制治療，其中該一或多個HLA-C SNP係選自由以下組成之群：rs2394952、rs3130542、rs2894202、rs9264523、rs1049281、rs9264643、rs1130838、rs2394888、AX-83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688、rs3130536及rs3134750，或其互補序列。The viral suppression therapy of any one of claims 24 to 31, wherein the one or more HLA-C SNPs are selected from the group consisting of: rs2394952, rs3130542, rs2894202, rs9264523, rs1049281, rs9264643, rs1130838, rs2394888, AX -83089411、rs2308622、rs9264416、rs2001181、rs3132499、rs3130532、rs3130941、rs3130528、rs3134782、rs3134769、rs3130521、rs3130695、rs3130685、rs2524119、rs3130527、rs2894186、rs3130439、rs3095254、rs9264189、rs2394943、rs9394047、rs3130948、rs9368666、rs3130942、rs3130688 , rs3130536 and rs3134750, or their complements. 如請求項24至31中任一項之病毒抑制治療，其中該一或多個HLA-C SNP係選自由rs4084090、rs9264127、rs9264039及rs3868078或其互補序列組成之群。The viral suppression therapy of any one of claims 24 to 31, wherein the one or more HLA-C SNPs are selected from the group consisting of rs4084090, rs9264127, rs9264039 and rs3868078 or their complements. 如請求項24至33中任一項之病毒抑制治療，其中該HED分數係選自由HED HLA-A大於3.88之值、HED HLA-B大於9.37之值、HED HLA-C大於0.00之值、平均HED HLA I類大於8.69之值、HED HLA-DPB1大於2.21之值、HED HLA-DQB1大於11.98之值、HED HLA-DRB1大於12.68之值及平均HED HLA II類大於7.55之值組成之群。The viral suppression therapy of any one of claims 24 to 33, wherein the HED score is selected from the group consisting of HED HLA-A greater than 3.88, HED HLA-B greater than 9.37, HED HLA-C greater than 0.00, average A group consisting of HED HLA class I values greater than 8.69, HED HLA-DPB1 values greater than 2.21, HED HLA-DQB1 values greater than 11.98, HED HLA-DRB1 values greater than 12.68 and average HED HLA class II values greater than 7.55. 如請求項24至33中任一項之病毒抑制治療，其中該HED分數係選自由HED HLA-A大於3.88之值及平均HED HLA II類大於7.67之值組成之群。The viral suppression therapy of any one of claims 24 to 33, wherein the HED score is selected from the group consisting of a HED HLA-A value greater than 3.88 and a mean HED HLA class II value greater than 7.67. 如請求項24至33中任一項之病毒抑制治療，其中該HED分數係選自由HED HLA-C大於7.37之值、平均HED HLA I類大於7.61之值、HED HLA-DRB1大於14.16之值及平均HED HLA II類大於8.21之值組成之群。The viral suppression therapy of any one of claims 24 to 33, wherein the HED score is selected from the group consisting of HED HLA-C greater than 7.37, mean HED HLA class I value greater than 7.61, HED HLA-DRB1 greater than 14.16, and A group consisting of values with an average HED HLA class II greater than 8.21. 如請求項24至36中任一項之病毒抑制治療，其中該一或多個LCR SNP係選自由以下組成之群：rs10426302、rs59537494、rs28366008、rs36625、rs635608、rs7595、rs731170、rs28513、rs12459334、rs11666535、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627，或其互補序列。The viral suppression therapy of any one of claims 24 to 36, wherein the one or more LCR SNPs are selected from the group consisting of: rs10426302, rs59537494, rs28366008, rs36625, rs635608, rs7595, rs731170, rs28513, rs12459334, rs11666535 、rs4806807、rs11084367、rs39714、rs1654474、rs12462907、rs775893、rs10416527、rs4441391、rs40167、rs11084339、rs775875、rs2304225、rs4077076、rs4442924、rs4806527、rs12608979、COSV52557220之rs3765013、rs12462181、COSV52550169之rs2075731、rs12608988、rs190480734、rs1654452、rs11879415 、rs653560、rs11084387、rs11672111、rs10424969、rs77389424、CM1111041之rs3745902、rs11672983、rs17836364、rs34549987、rs11668526、rs11667105、rs1749282、rs1654660、rs73618328、rs270785、rs76522818、rs62131745、rs2241384、rs1325158、rs10500318、rs3816051、rs34508934及rs12460627，或its complementary sequence. 如請求項24至36中任一項之病毒抑制治療，其中該一或多個LCR SNP係選自由以下組成之群：rs11667812、rs12974194、rs17836364、rs11669431、rs12984962、rs1761462、rs4806464、rs34190750、rs28681595、rs12610675、rs12463051、rs1749282、rs1654660、rs41275824、rs2241384、rs12983338、rs272408、rs10412569、AX-3232794851、rs622941及rs60690598，或其互補序列。The viral suppression therapy of any one of claims 24 to 36, wherein the one or more LCR SNPs are selected from the group consisting of: rs11667812, rs12974194, rs17836364, rs11669431, rs12984962, rs1761462, rs4806464, rs34190750, rs286751595, rs12611 , rs12463051, rs1749282, rs1654660, rs41275824, rs2241384, rs12983338, rs272408, rs10412569, AX-3232794851, rs622941, and rs60690598, or their complements. 如請求項24至38中任一項之病毒抑制治療，其中該SNP或該對偶基因係藉由選自由以下組成之群之方法來判定：DNA定序、限制片段長度多型性(RFLP分析)、對偶基因特異性寡核苷酸(ASO)分析、變性/溫度梯度凝膠電泳(DGGE/TGGE)、單股構象多型性(SSCP)分析、雙去氧指紋分析(ddF)、焦磷酸定序分析、acycloprime分析、反向墨點轉漬、基因晶片(GeneChip)微陣列、動態對偶基因特異性雜交(DASH)、肽核酸(PNA)及鎖核酸(LNA)探針、TaqMan、分子信標、嵌入染料、FRET引子、AlphaScreen、SNPstream、遺傳位元分析(GBA)、多重微定序、SNaPshot、MassEXTEND、MassArray、GOOD檢定、微陣列微定序、陣列式引子延伸(APEX)、微陣列引子延伸、標籤陣列、經編碼之微球、模板導向併入(TDI)、螢光偏振、比色寡核苷酸連接檢定(OLA)、序列編碼OLA、微陣列連接、連接酶鏈反應、扣鎖(Padlock)探針、滾環擴增及侵入物(Invader)檢定。The viral suppression therapy of any one of claims 24 to 38, wherein the SNP or the counterpart gene is determined by a method selected from the group consisting of DNA sequencing, restriction fragment length polymorphism (RFLP analysis) , Dual gene-specific oligonucleotide (ASO) analysis, denaturation/temperature gradient gel electrophoresis (DGGE/TGGE), single-strand conformation polymorphism (SSCP) analysis, dideoxy fingerprint analysis (ddF), pyrophosphorylation Sequencing analysis, acycloprime analysis, reverse blotting, GeneChip microarray, dynamic dual gene-specific hybridization (DASH), peptide nucleic acid (PNA) and locked nucleic acid (LNA) probes, TaqMan, molecular beacons , Intercalating Dyes, FRET Primers, AlphaScreen, SNPstream, Genetic Bit Analysis (GBA), Multiplex Microsequencing, SNaPshot, MassEXTEND, MassArray, GOOD Assay, Microarray Microsequencing, Arrayed Primer Extension (APEX), Microarray Primers Extension, tag array, encoded microspheres, template-directed incorporation (TDI), fluorescence polarization, colorimetric oligonucleotide ligation assay (OLA), sequence-encoded OLA, microarray ligation, ligase chain reaction, snap-lock (Padlock) probe, rolling circle amplification and Invader assay. 如請求項24至39中任一項之病毒抑制治療，其中該病毒抑制劑係核苷酸或核苷類似物(NUC)，及該NUC係選自由替諾福韋、恩替卡韋、拉米夫定、阿德福韋及替比夫定組成之群。The viral suppression therapy of any one of claims 24 to 39, wherein the viral inhibitor is a nucleotide or nucleoside analog (NUC), and the NUC is selected from tenofovir, entecavir, lamivudine , adefovir and telbivudine. 如請求項24至40中任一項之病毒抑制治療，其中，當該個體達成HBV DNA ＜ 60 IU/mL、丙胺酸轉胺酶(ALT) ＜ 80 U/L及B型肝炎e抗原(HBeAg)陰性中之至少一者時，該個體中止該病毒抑制治療。The viral suppression therapy of any one of claims 24 to 40, wherein, when the individual achieves HBV DNA < 60 IU/mL, alanine aminotransferase (ALT) < 80 U/L, and hepatitis B e antigen (HBeAg ) negative, the subject discontinues the viral suppression therapy. 如請求項41之病毒抑制治療，其中該個體於該病毒抑制治療中止之時進一步達成HBsAg ＜ 100 IU/mL。The viral suppression therapy of claim 41, wherein the subject further achieves HBsAg < 100 IU/mL at the time of discontinuation of the viral suppression therapy. 如請求項24至42中任一項之病毒抑制治療，其中該個體在中止該病毒抑制治療之後的3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間時或之後沒有病毒學復發，且該病毒學復發經識別為HBV DNA ≥ 2000 IU/ml或HBeAg陽性。The viral suppression therapy of any one of claims 24 to 42, wherein the subject is 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months after discontinuation of the viral suppression therapy or There was no virological relapse at or after any time in between, and the virological relapse was identified as HBV DNA ≥ 2000 IU/ml or HBeAg positive. 如請求項24至42中任一項之病毒抑制治療，其中該個體在中止該病毒抑制治療之後的3個月、6個月、12個月、18個月、24個月或36個月或其間的任何時間或之後沒有臨床復發，且該臨床復發經識別為i) HBV DNA ≥ 2000 IU/ml或HBeAg陽性，且ii) ALT ≥ 80 U/L。The viral suppression therapy of any one of claims 24 to 42, wherein the subject is 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months after discontinuation of the viral suppression therapy or There was no clinical relapse at any time during or afterward, and the clinical relapse was identified as i) HBV DNA ≥ 2000 IU/ml or HBeAg positive, and ii) ALT ≥ 80 U/L. 如請求項24至44中任一項之病毒抑制治療，其中該生物樣本係組織樣本、細胞樣本或血液樣本。The viral suppression therapy of any one of claims 24 to 44, wherein the biological sample is a tissue sample, a cell sample or a blood sample. 一種組合，其用於預測有需要個體在治療慢性B型肝炎(CHB)感染之病毒抑制之後的低復發風險，該組合包含能夠偵測如請求項1至45中任一項之免疫遺傳生物標記中之一者或多者之試劑。A combination for predicting a low risk of relapse in an individual in need following viral suppression in the treatment of chronic hepatitis B (CHB) infection, the combination comprising an immunogenetic biomarker capable of detecting any one of claims 1 to 45 One or more of the reagents. 如請求項46之組合，其進一步包含一或多種用於治療該CHB之治療劑。The combination of claim 46, further comprising one or more therapeutic agents for treating the CHB. 一種用於血清學HLA分型之套組或一種用於遺傳HLA分型之套組，其用於預測病毒抑制劑於治療有需要個體中慢性B型肝炎(CHB)感染之功效。A panel for serological HLA typing or a panel for genetic HLA typing for predicting the efficacy of viral inhibitors in the treatment of chronic hepatitis B (CHB) infection in individuals in need. 如請求項48之套組，其偵測如請求項1至45中任一項之方法之該一或多個免疫遺傳生物標記。The kit of claim 48 that detects the one or more immunogenetic biomarkers of the method of any one of claims 1-45.
TW110132421A 2020-09-02 2021-09-01 Biomarkers and uses thereof in the treatment of chronic hbv infection TW202214873A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063073617P 2020-09-02 2020-09-02
US63/073,617 2020-09-02

Publications (1)

Publication Number Publication Date
TW202214873A true TW202214873A (en) 2022-04-16

Family

ID=77655593

Family Applications (1)

Application Number Title Priority Date Filing Date
TW110132421A TW202214873A (en) 2020-09-02 2021-09-01 Biomarkers and uses thereof in the treatment of chronic hbv infection

Country Status (6)

Country Link
US (1) US20220090217A1 (en)
EP (1) EP4208569A2 (en)
AU (1) AU2021337850A1 (en)
CA (1) CA3191106A1 (en)
TW (1) TW202214873A (en)
WO (1) WO2022049504A2 (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080299125A1 (en) 2006-06-05 2008-12-04 Perlegen Sciences, Inc. Genetic basis of treatment response in depression patients
WO2018223185A1 (en) * 2017-06-06 2018-12-13 Gmdx Co Pty Ltd Methods of determining the likelihood of hepatitis b virus recrudescence
CN115066505A (en) * 2020-02-06 2022-09-16 爱尔兰詹森科学公司 Biomarkers and their use in treating chronic hepatitis B infection

Also Published As

Publication number Publication date
EP4208569A2 (en) 2023-07-12
WO2022049504A2 (en) 2022-03-10
WO2022049504A3 (en) 2022-06-09
US20220090217A1 (en) 2022-03-24
CA3191106A1 (en) 2022-03-10
AU2021337850A1 (en) 2023-03-09

Similar Documents

Publication Publication Date Title
US20090305900A1 (en) Genemap of the human genes associated with longevity
JP6496003B2 (en) Genetic marker for predicting responsiveness to FGF-18 compounds
IL194900A (en) Hla alleles associated with adverse drug reactions and methods for detecting such
WO2011146985A1 (en) Method of determining response to treatment with immunomodulatory composition
US20230332230A1 (en) Biomarkers and uses thereof in the treatment of chronic hepatitis b infection
CN115679003A (en) Compositions, systems and uses for predicting drug efficacy
JP2023055222A (en) Human genetic markers associated with response to treatments that target clostridium difficile toxin b
TWI479024B (en) Method for determining p1/p2 blood type and detection kit thereof
TWI579722B (en) Method for assessing the risk of adverse drug reaction and device thereof
TW202214873A (en) Biomarkers and uses thereof in the treatment of chronic hbv infection
CN107849041B (en) Genetic markers associated with response to CRTH2 receptor antagonists
JP2017502663A (en) Biomarkers for HBV treatment response
US20200017909A1 (en) Human genetic markers associated with response to treatments that target clostridium difficile toxin b
US20220177982A1 (en) Methods Of Identifying Subjects Having An Increased Risk Of Developing A Coronavirus Infection And Treatment Thereof
Riazalhosseini et al. Prevalence of HLA-DQ alleles and haplotypes in patients with hepatitis B infection
WO2015037681A1 (en) Test method for evaluating the risk of anti-thyroid drug-induced agranulocytosis, and evaluation kit
US20140302013A1 (en) Predicting and diagnosing patients with systemic lupus erythematosus
JP2018500903A (en) Biomarkers for HBV treatment response
CN117363799A (en) Composition, product and system for predicting effect of interferon drug on treating chronic hepatitis B
Vermehren et al. A Common HLA-DPA1 Variant Is Associated with Hepatitis B Virus Infection but Fails to
Morgan et al. Quantitative Trait Locus and Brain Expression of HLA-DPA1 Offers Evidence of Shared
EP2576821A1 (en) Biomarkers
JP2018519839A (en) Biomarkers for HBV treatment response